Science.gov

Sample records for adipocyte-derived hormone leptin

  1. [Leptin: adipocyte hormone].

    PubMed

    Castagna, L; De Gregorio, T; Allegra, A; Buemi, M; Corsonello, A; Bonanzinga, S; Catanoso, M; Ceruso, D; Corica, F

    1998-04-01

    The authors reviewed the most recent literature on leptin, a protein produced by adipocytes which exerts its action on hypothalamus, modifying eating behavior and inhibiting the lust for food consumption. This one appeared to be the main, if not the only, physiologic action of leptin. Later leptin has been acknowledged a major role in the homeostasis. The regulation of the synthesis, and the mechanisms by which the protein modulates both food intake and energetic balance have been evaluated, and the hypotheses on the regulatory function exerted by leptin on the homeostasis, by acting on neuroendocrine system, on sexual maturity and fertility, on the sympathetic nervous system, on hemopoiesis and hydroelectrolytic balance have been discussed, some of which being already supported by experimental evidences.

  2. Leptin activates chicken growth hormone promoter without chicken STAT3 in vitro.

    PubMed

    Murase, Daisuke; Namekawa, Shoko; Ohkubo, Takeshi

    2016-01-01

    Leptin is an adipocyte-derived hormone that not only regulates food intake and energy homeostasis but also induces growth hormone (GH) mRNA expression and release, thereby controlling growth and metabolism in mammals. The molecular mechanism of leptin-induced regulation of GH gene transcription is unclear. The current study investigated the effects of leptin on the chicken GH (cGH) promoter and the molecular mechanism underlying leptin-induced cGH gene expression in vitro. Leptin activated the cGH promoter in the presence of chPit-1α in CHO cells stably expressing the chicken leptin receptor. Promoter activation did not require STAT-binding elements in the cGH promoter or STAT3 activity. However, JAK2 activation was required for leptin-dependent activity. JAK2-dependent pathways include p42/44 MAPK and PI3K, and inhibition of these pathways partially blocked leptin-induced cGH gene transcription. Although CK2 directly activates JAK2, a CK2 inhibitor blocked leptin-dependent activation of the cGH gene without affecting JAK2 phosphorylation. The CK2 inhibitor suppressed Erk1/2 and Akt phosphorylation. Additional data implicate Src family kinases in leptin-dependent cGH gene activation. These results suggest that leptin activates the cGH gene in the presence of chPit-1α via several leptin-activated kinases. Although further study is required, we suggest that the leptin-induced JAK2/p42/44 MAPK and JAK2/PI3K cascades are activated by Src-meditated CK2, leading to CBP phosphorylation and interaction with chPit-1α, resulting in transactivation of the cGH promoter.

  3. Thyroid Hormone and Leptin in the Testis

    PubMed Central

    Ramos, Cristiane Fonte; Zamoner, Ariane

    2014-01-01

    Leptin is primarily expressed in white adipose tissue; however, it is expressed in the hypothalamus and reproductive tissues as well. Leptin acts by activating the leptin receptors (Ob-Rs). Additionally, the regulation of several neuroendocrine and reproductive functions, including the inhibition of glucocorticoids and enhancement of thyroxine and sex hormone concentrations in human beings and mice are leptin functions. It has been suggested that thyroid hormones (TH) could directly regulate leptin expression. Additionally, hypothyroidism compromises the intracellular integration of leptin signaling specifically in the arcuate nucleus. Two TH receptor isoforms are expressed in the testis, TRa and TRb, with TRa being the predominant one that is present in all stages of development. The effects of TH involve the proliferation and differentiation of Sertoli and Leydig cells during development, spermatogenesis, and steroidogenesis. In this context, TH disorders are associated with sexual dysfunction. An endocrine and/or direct paracrine effect of leptin on the gonads inhibits testosterone production in Leydig cells. Further studies are necessary to clarify the effects of both hormones in the testis during hypothyroidism. The goal of this review is to highlight the current knowledge regarding leptin and TH in the testis. PMID:25505448

  4. Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats

    PubMed Central

    Watanobe, Hajime

    2002-01-01

    It is still not known whether leptin, an adipocyte-derived hormone, acts directly within the hypothalamus to stimulate the gonadotropin-releasing hormone (GnRH)-luteinizing hormone (LH) system. In order to address this question, the present study examined the effects of direct intrahypothalamic perfusions with leptin on the in vivo release of GnRH in ovarian steroid-primed ovariectomized rats utilizing the push-pull perfusion technique. Both α-melanocyte-stimulating hormone (α-MSH) and neuropeptide Y were also measured in the hypothalamic perfusates. In normally fed animals, the leptin infusion was without effect on the release of these three hypothalamic peptides and also without effect on plasma LH and prolactin (PRL), whether leptin was infused into the medial preoptic area (where the majority of GnRH neuronal cell bodies exist) or the median eminence-arcuate nucleus complex (where axon terminals of GnRH neurons are located). In contrast, in 3-day fasted rats leptin was effective in stimulating the secretion of GnRH, α-MSH, and LH, regardless of the site of perfusion. These three hormones were increased in a temporal order of α-MSH, GnRH and LH. Irrespective of the site of perfusion, leptin was without effect on the release of neuropeptide Y. Only when leptin was infused into the median eminence-arcuate nucleus complex was PRL secretion also stimulated, although its onset was 1 h behind that of LH. The leptin-induced elevations of GnRH, α-MSH, LH and PRL were all dose-dependently stimulated by subnormal (1.0 ng ml−1) and normal (3.0 ng ml−1) concentrations of leptin, but at higher concentrations (10 ng ml−1) it did not produce additional effects. Leptin infusion into the anterior hypothalamic area, a control site equidistant from both the medial preoptic area and the median eminence-arcuate nucleus complex, did not produce a significant change in any of the hormones in either the fed or fasted rats. These results demonstrate for the first time that

  5. Behavioral, hormonal and central serotonin modulating effects of injected leptin.

    PubMed

    Haleem, Darakhshan J; Haque, Zeba; Inam, Qurrat-ul-Aen; Ikram, Huma; Haleem, Muhammad Abdul

    2015-12-01

    Leptin is viewed as an important target for developing novel therapeutics for obesity, depression/anxiety and cognitive dysfunctions. The present study therefore concerns behavioral, hormonal and central serotonin modulating effects of systemically injected leptin. Pharmacological doses (100 and 500 μg/kg) of leptin injected systemically decreased 24h cumulative food intake and body weight in freely feeding rats and improved acquisition and retention of memory in Morris water maze test. Potential anxiety reducing, hormonal and serotonin modulating effects of the peptide hormone were determined in a separate experiment. Animals injected with 100 or 500 μg/kg leptin were tested for anxiety in an elevated plus maze test 1h later. A significant increase in the number of entries and time passed in open arm of the elevated plus maze in leptin injected animals suggested pronounced anxiety reducing effect. Moreover, circulating levels of leptin correlated significantly with anxiety reducing effects of the peptide hormone. Serum serotonin increased and ghrelin decreased in leptin injected animals and correlated, positively and negatively respectively, with circulating leptin. Corticosterone increased at low dose and levels were normal at higher dose. Serotonin metabolism in the hypothalamus and hippocampus decreased only at higher dose of leptin. The results support a role of leptin in the treatment of obesity, anxiety and cognitive dysfunctions. It is suggested that hormonal and serotonin modulating effects of leptin can alter treatment efficacy in particularly comorbid conditions.

  6. DNA Methylation Suppresses Leptin Gene in 3T3-L1 Adipocytes

    PubMed Central

    Kuroda, Masashi; Tominaga, Ayako; Nakagawa, Kasumi; Nishiguchi, Misa; Sebe, Mayu; Miyatake, Yumiko; Kitamura, Tadahiro; Tsutsumi, Rie; Harada, Nagakatsu; Nakaya, Yutaka; Sakaue, Hiroshi

    2016-01-01

    Leptin is a key regulator of energy intake and expenditure. This peptide hormone is expressed in mouse white adipose tissue, but hardly expressed in 3T3-L1 adipocytes. Using bisulfite sequencing, we found that CpG islands in the leptin promoter are highly methylated in 3T3-L1cells. 5-azacytidine, an inhibitor of DNA methyltransferase, markedly increased leptin expression as pre-adipocytes matured into adipocytes. Remarkably, leptin expression was stimulated by insulin in adipocytes derived from precursor cells exposed to 5-azacytidine, but suppressed by thiazolidinedione and dexamethasone. In contrast, adipocytes derived from untreated precursor cells were unresponsive to both 5-azacytidine and hormonal stimuli, although lipid accumulation was sufficient to boost leptin expression in the absence of demethylation. Taken together, the results suggest that leptin expression in 3T3-L1 cells requires DNA demethylation prior to adipogenesis, transcriptional activation during adipogenesis, and lipid accumulation after adipogenesis. PMID:27494408

  7. Episodic leptin release is independent of luteinizing hormone secretion.

    PubMed

    Sir-Petermann, T; Maliqueo, M; Palomino, A; Vantman, D; Recabarren, S E; Wildt, L

    1999-11-01

    Several studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate release of gonadotrophin releasing hormone (GnRH) from the hypothalamus and of gonadotrophins from the pituitary. A synchronicity of luteinizing hormone (LH) and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome, suggesting that leptin may modulate the episodic secretion of LH. However, it has not been established whether LH regulates the episodic secretion of leptin. To further examine LH-leptin interactions, we studied the episodic fluctuations of circulating LH and leptin in two patients with Kallmann's syndrome (KS) before and on day 7 of pulsatile GnRH administration, and compared these with those observed in the early follicular phase of 10 regularly menstruating women divided into two control groups according to the body mass index of each patient. To assess episodic hormone secretion, blood samples were collected at 10 min intervals for 6 h, before and on day 7 of GnRH administration in KS patients, and during days 3-7 of the follicular phase in normally cycling women. LH and leptin concentrations were measured in all samples. For pulse analysis, the cluster algorithm was used. Before treatment, an apulsatile pattern with no endogenous LH pulsations was observed in both KS patients. However, leptin pulses were assessed in both women. During GnRH administration, pulsatile LH activity was achieved in both patients with pulse characteristics similar to those of the respective control group. Serum leptin concentrations and leptin pulsatile patterns were not modified. These results suggest that circulating leptin is probably not modulated by pulsatile GnRH-LH secretion.

  8. Human leptin: from an adipocyte hormone to an endocrine mediator.

    PubMed

    Wauters, M; Considine, R V; Van Gaal, L F

    2000-09-01

    Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic-pituitary-adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic-pituitary-gonadal axis and on insulin metabolism, but also on the hypothalamic-pituitary-adrenal, thyroid and GH axes. Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

  9. [Leptin].

    PubMed

    Nedvídková, J

    1997-12-01

    Leptin (ob-protein), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks, that regulate weight and energy homeostasis. Leptin provides a communication link between fat tissue and the brain. Ob protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. Leptin levels have pulsative and diurnal character. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form. On other hand, in obese individuals the majority of leptin circulates in free form presumably bioactive protein, and thus obese subjects are resistant to free leptin. Leptin's resistance is often coupled with insuline resistance postreceptor type. Leptin receptor is product of db genes. Ob-protein receptor belongs to the cytokine superfamily of receptors and has several variants. Leptin-receptor gene is expressed in abundant degree in ovary, uterus, testes, less in hypothalamus, hypophysis, and little in kidney. Leptin stimulates the reproductive endocrine system and may serve as a permissive signal to the reproductive system of normal animals. Ob-gene product, leptin is regulated by feedings patterns and hormones, such as insulin and glucocorticoids. There is assumed that neuropeptide Y (NPY) and melanocyte-stimulating hormone (MSH) and its receptor (MCR) are a critical components of the biological response to leptin levels. MCR in contrast to leptin receptors are coupled with G-transduction system.

  10. Leptin: From structural insights to the design of antagonists.

    PubMed

    Zabeau, Lennart; Peelman, Frank; Tavernier, Jan

    2015-11-01

    After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormone with a central role in the control of body weight and energy homeostasis. However, a growing body of evidence has revealed that leptin is a pleiotropic cytokine with activities on many peripheral cell types. Inappropriate leptin signaling can promote autoimmunity, certain cardiovascular diseases, elevated blood pressure and cancer, which makes leptin and the leptin receptor interesting targets for antagonism. Profound insights in the leptin receptor (LR) activation mechanisms are a prerequisite for the rational design of these antagonists. In this review, we focus on the molecular mechanisms underlying leptin receptor activation and signaling. We also discuss the current strategies to interfere with leptin signaling and their therapeutic potential.

  11. Drug targeting of leptin resistance.

    PubMed

    Santoro, Anna; Mattace Raso, Giuseppina; Meli, Rosaria

    2015-11-01

    Leptin regulates glucose, lipid and energy homeostasis as well as feeding behavior, serving as a bridge between peripheral metabolically active tissues and the central nervous system (CNS). Indeed, this adipocyte-derived hormone, whose circulating levels mirror fat mass, not only exerts its anti-obesity effects mainly modulating the activity of specific hypothalamic neurons expressing the long form of the leptin receptor (Ob-Rb), but it also shows pleiotropic functions due to the activation of Ob-Rb in peripheral tissues. Nevertheless, several mechanisms have been suggested to mediate leptin resistance, including obesity-associated hyperleptinemia, impairment of leptin access to CNS and the reduction in Ob-Rb signal transduction effectiveness, among others. During the onset and progression of obesity, the dampening of leptin sensitivity often occurs, preventing the efficacy of leptin replacement therapy from overcoming obesity and/or its comorbidities. This review focuses on obesity-associated leptin resistance and the mechanisms underpinning this condition, to highlight the relevance of leptin sensitivity restoration as a useful therapeutic strategy to treat common obesity and its complications. Interestingly, although promising strategies to counteract leptin resistance have been proposed, these pharmacological approaches have shown limited efficacy or even relevant adverse effects in preclinical and clinical studies. Therefore, the numerous findings from this review clearly indicate a lack of a single and efficacious treatment for leptin resistance, highlighting the necessity to find new therapeutic tools to improve leptin sensitivity, especially in patients with most severe disease profiles.

  12. The effects of protein supplement on leptin concentrations in lambs and meat goat kids grazing Bermudagrass pastures in Central Oklahoma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lambs and kids weaned and pastured on bermudagrass (BG; Cynodon dactylon) may not receive enough protein to reach maximal growth during mid to late summer when protein in BG pastures declines. As an indicator of physiological status, leptin is an adipocyte-derived hormone that increases as body cond...

  13. Serum Leptin and Insulin Hormone Level in Recurrent Pregnancy Loss

    PubMed Central

    Baban, Rayah S.; Ali, Noor M.; Al-Moayed, Hala A.

    2010-01-01

    Objective To measure serum leptin and insulin levels in women with recurrent pregnancy loss using modified methods of High Performance Liquid Chromatography (HPLC), and to examine their influence on recurrent loss at different pregnancy trimesters. Methods A case control study was conducted from, 1 September 2008 to 30 December 2009 in the Obstetric and Gynecological Department-Al-Khadimiya Teaching Hospital. HPLC technique with new modified method was used to estimate serum leptin and insulin hormones in samples of women with recurrent pregnancy loss (patients group, n=64) and healthy pregnant women at the end of the third gestational trimester as a control group (n=51). Results Both serum leptin and insulin levels were high in women with pregnancy loss in their three trimesters. A significant correlation was found between age (r=0.535, p<0.018) and serum total leptin in women with RPL during the first trimester. Also, a highly significant correlation was found between serum total leptin and insulin in women with RPL during the first, second and third trimesters (r=0.894, r=0.931, and r =0.995) respectively. The number of women who lost their pregnancy during the first trimester was higher than those losing during other trimesters. Conclusion It can be concluded that recurrent pregnancy loss in women at different trimester is associated with endocrine abnormalities where serum leptin and insulin levels increase in a different way compared with normal healthy pregnant women. PMID:22043338

  14. A heliocentric view of leptin.

    PubMed

    Frühbeck, G

    2001-08-01

    Leptin is significantly broadening our understanding of the mechanisms underlying neuroendocrine function. Initially, based on a rather static view of the hormone, most investigations focused on the effects of leptin on food intake control and body-weight homeostasis, with attention primarily focused on the implications of leptin as a lipostatic factor and central satiety agent. However, the almost ubiquitous distribution of leptin receptors in peripheral tissues provided a fertile area for investigation and a more dynamic view of leptin started to unfold. This adipocyte-derived circulating peptidic hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family, has generated an enormous interest in the interaction as well as integration between brain targets and peripheral signals. Considerable evidence for systemic effects of leptin on specific tissues and metabolic pathways indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Disentangling the biochemical and molecular mechanisms in which leptin is involved represents one of the major challenges ahead.

  15. Adipocyte Versus Pituitary Leptin in the Regulation of Pituitary Hormones: Somatotropes Develop Normally in the Absence of Circulating Leptin

    PubMed Central

    Odle, Angela K.; Haney, Anessa; Allensworth-James, Melody; Akhter, Noor

    2014-01-01

    Leptin is a cytokine produced by white fat cells, skeletal muscle, the placenta, and the pituitary gland among other tissues. Best known for its role in regulating appetite and energy expenditure, leptin is produced largely by and in proportion to white fat cells. Leptin is also important to the maintenance and function of the GH cells of the pituitary. This was shown when the deletion of leptin receptors on somatotropes caused decreased numbers of GH cells, decreased circulating GH, and adult-onset obesity. To determine the source of leptin most vital to GH cells and other pituitary cell types, we compared two different leptin knockout models with Cre-lox technology. The global Lep-null model is like the ob/ob mouse, whereby only the entire exon 3 is deleted. The selective adipocyte-Lep-null model lacks adipocyte leptin but retains pituitary leptin, allowing us to investigate the pituitary as a potential source of circulating leptin. Male and female mice lacking adipocyte leptin (Adipocyte-lep-null) did not produce any detectable circulating leptin and were infertile, suggesting that the pituitary does not contribute to serum levels. In the presence of only pituitary leptin, however, these same mutants were able to maintain somatotrope numbers and GH mRNA levels. Serum GH trended low, but values were not significant. However, hypothalamic GHRH mRNA was significantly reduced in these animals. Other serum hormone and pituitary mRNA differences were observed, some of which varied from previous results reported in ob/ob animals. Whereas pituitary leptin is capable of maintaining somatotrope numbers and GH mRNA production, the decreased hypothalamic GHRH mRNA and low (but not significant) serum GH levels indicate an important role for adipocyte leptin in the regulation of GH secretion in the mouse. Thus, normal GH secretion may require the coordinated actions of both adipocyte and pituitary leptin. PMID:25116704

  16. Sex steroids, growth hormone, leptin and the pubertal growth spurt.

    PubMed

    Rogol, Alan D

    2010-01-01

    A normal rate for the linear growth of a child or adolescent is a strong statement for the good general health of that child. Normal growth during childhood is primarily dependent on adequate nutrition, an adequate psychosocial environment, the absence of disease and adequate amounts thyroid hormone and growth hormone (and its downstream product, IGF-1). At adolescence there is the reawakening of the hypothalamic-pituitary-gonadal axis and its interaction with the GH/IGF-1 axis to subserve the pubertal growth spurt. The fat tissue-derived hormone, leptin and its receptor are likely involved in at least two aspects of pubertal development - sexual development itself and the alterations in body composition including the regional distribution of fat and bone mineralization. During the prepubertal years the male female differences in body composition are quite modest, but change remarkably during pubertal development with boys showing a relative decrement in fat percentage and girls a marked increase in concert with rising levels of circulating leptin. The boys show a much greater increase in lean body tissue and the relative proportions of water, muscle and bone. These may be observed as the differential growth of the shoulders and hips. The net effect of these pubertal changes is that the young adult woman has approximately 25% body fat in the 'gynoid' distribution while the male has much more muscle, especially in the shoulders and upper body but only approximately 13% body fat.

  17. Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?

    PubMed

    Sir-Petermann, T; Piwonka, V; Pérez, F; Maliqueo, M; Recabarren, S E; Wildt, L

    1999-06-01

    Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and

  18. Leptin in male reproduction: the testis paradigm.

    PubMed

    Tena-Sempere, M; Barreiro, M L

    2002-02-25

    Leptin, the adipocyte-derived hormone that plays a key role in body weight homeostasis, has recently emerged as a relevant neuroendocrine mediator in different systems, including the reproductive axis. Thus, compelling evidence points out a major role of leptin in the regulation of female pubertal development and fertility, both in humans and experimental animals. The contribution of leptin to the proper functioning of the male reproductive system has been less clear. However, data gathered in recent years, from independent groups and through a variety of experimental approaches, strongly suggest that leptin is able to act at different levels of the hypothalamic-pituitary-testicular axis. Herein, we review the biological effects and potential mechanisms of action of leptin upon rodent testis. Leptin appears to act as a direct inhibitory signal for testicular steroidogenesis, which may be relevant to explain the link between decreased testosterone secretion and hyperleptinaemia in obese men. Analysis of the molecular basis for leptin-induced inhibition of testosterone secretion revealed the potential involvement of decreased gene expression of several up-stream factors (e.g. SF-1, StAR and P450scc) in the steroidogenic pathway. In this context, testicular expression of leptin receptor (Ob-R) gene shows a complex pattern of alternative splicing with generation of multiple variants, including the functional leptin receptor type-b (Ob-Rb) and several short isoforms. Moreover, Ob-R mRNA expression in rat testis was regulated by homologous (leptin) as well as heterologous (gonadotropins) signals. Overall, the current data indicate that the testis is a direct target for leptin actions. Furthermore, the available evidence is suggestive of a tightly regulated, complex mode of action of leptin at different levels of the male gonadal axis that involves not only stimulatory but also inhibitory effects.

  19. Expression and immunohistochemical localization of leptin in human periapical granulomas

    PubMed Central

    Martín-González, Jénifer; Carmona-Fernández, Antonio; Pérez-Pérez, Antonio; Sánchez-Jiménez, Flora; Sánchez-Margalet, Víctor

    2015-01-01

    Background Leptin, initially described as an adipocyte-derived hormone to regulate weight control, is expressed in normal and inflamed human dental pulp, being up-regulated during pulp experimental inflammation. Leptin receptor (LER) has been identified in human periapical granulomas. The aim of this study was to analyze and characterize the expression of leptin in human periapical granulomas. Material and Methods Fifteen periapical inflammatory lesions were obtained from extracted human teeth and teeth which underwent periapical surgery. After their morphological categorization as periapical granulomas and gradation of the inflammatory infiltrate, they were examined by immunohistochemistry using human leptin policlonal antibodies. Leptin mRNA expression was also determined by quantitative real-time PCR (qRT-PCR) and the amount of leptin protein was analyzed by immunoblot. Results All periapical lesions exhibited the characteristic of chronic granulomatous inflammatory process with inflammatory infiltrate grade III. Leptin+ cells were detected in 13 periapical granulomas (86.6%). The median number of Leptin+ cells in periapical granulomas was 1.70 (0.00-7.4). Amongst the inflammatory cells in the periapical granulomas, only macrophages were reactive to leptin antibodies. Western blot analysis revealed the presence in all samples of a protein with apparent molecular weight of approximately 16 kDa, corresponding to the estimated molecular weights of leptin. The expression of leptin mRNA was confirmed by qRT-PCR analysis and the size of the amplified fragment (296 bp for leptin and 194 bp for cyclophilin) was assessed by agarose gel electrophoresis. Conclusions For the first time, it has been demonstrated that human periapical granuloma expresses the adipokine leptin. Key words: Apical granuloma, dental pulp, endodontics, leptin, leptin receptor, immune system, immunohistochemistry, periapical inflammatory response. PMID:25662559

  20. Leptin stimulates hepatic activation of thyroid hormones and promotes early posthatch growth in the chicken.

    PubMed

    Li, Rongjie; Hu, Yan; Ni, Yingdong; Xia, Dong; Grossmann, Roland; Zhao, Ruqian

    2011-10-01

    Hepatic iodothyronine deiodinases (Ds) are involved in the conversion of thyroid hormones (THs) which interacts with growth hormone (GH) to regulate posthatch growth in the chicken. Previous studies suggest that leptin-like immunoreactive substance deposited in the egg may serve as a maternal signal to program posthatch growth. To test the hypothesis that maternal leptin may affect early posthatch growth through modifying hepatic activation of THs, we injected 5.0μg of recombinant murine leptin into the albumen of breeder eggs before incubation. Furthermore, chicken embryo hepatocytes (CEHs) were treated with leptin in vitro to reveal the direct effect of leptin on expression and activity of Ds. In ovo leptin administration markedly accelerated early posthatch growth, elevated serum levels of total and free triiodothyronine (tT3 and fT3), while that of total thyroxin (tT4) remained unchanged. Hepatic mRNA expression and activity of D1 which converts T4 to T3 or rT3 to T2, were significantly increased in leptin-treated chickens, while those of D3 which converts T3 to T2 or T4 to rT3, were significantly decreased. Moreover, hepatic expression of GHR and IGF-I mRNA was all up-regulated in leptin-treated chickens. Males demonstrated more pronounced responses. A direct effect of leptin on Ds was shown in CEHs cultured in vitro. Expression and activity of D1 were increased, whereas those of D3 were decreased, in leptin-treated cells. These data suggest that in ovo leptin administration improves early posthatch growth, in a gender-specific fashion, probably through improving hepatic activation of THs and up-regulating hepatic expression of GHR and IGF-I.

  1. Percentage of REM sleep is associated with overnight change in leptin.

    PubMed

    Olson, Christy A; Hamilton, Nancy A; Somers, Virend K

    2016-08-01

    Sleep contributes importantly to energy homeostasis, and may impact hormones regulating appetite, such as leptin, an adipocyte-derived hormone. There is increasing evidence that sleep duration, and reduced rapid eye movement sleep, are linked to obesity. Leptin has central neural effects beyond modulation of appetite alone. As sleep is not a unifrom process, interactions between leptin and sleep stages including rapid eye movement sleep may play a role in the relationship between sleep and obesity. This study examined the relationship between serum leptin and rapid eye movement sleep in a sample of healthy adults. Participants were 58 healthy adults who underwent polysomnography. Leptin was measured before and after sleep. It was hypothesized that a lower percentage of rapid eye movement sleep would be related to lower leptin levels during sleep. The relationship between percentage of rapid eye movement sleep and leptin was analysed using hierarchical linear regression. An increased percentage of rapid eye movement sleep was related to a greater reduction in leptin during sleep even when controlling for age, gender, percent body fat and total sleep time. A greater percentage of rapid eye movement sleep was accompanied by more marked reductions in leptin. Studies examining the effects of selective rapid eye movement sleep deprivation on leptin levels, and hence on energy homeostasis in humans, are needed. PMID:26919408

  2. Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin.

    PubMed

    Ogawa, Y; Masuzaki, H; Hosoda, K; Aizawa-Abe, M; Suga, J; Suda, M; Ebihara, K; Iwai, H; Matsuoka, N; Satoh, N; Odaka, H; Kasuga, H; Fujisawa, Y; Inoue, G; Nishimura, H; Yoshimasa, Y; Nakao, K

    1999-09-01

    Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.

  3. Anterior pituitary leptin expression changes in different reproductive states: in vitro stimulation by gonadotropin-releasing hormone.

    PubMed

    Akhter, Noor; Johnson, Brandy W; Crane, Christopher; Iruthayanathan, Mary; Zhou, Yi-Hong; Kudo, Akihiko; Childs, Gwen V

    2007-02-01

    This study was designed to learn more about the changes in expression of rat anterior pituitary (AP) leptin during the estrous cycle. QRT-PCR assays of cycling rat AP leptin mRNA showed 2-fold increases from metestrus to diestrus followed by an 86% decrease on the morning of proestrus. Percentages of leptin cells increased in proestrus and pregnancy to 55-60% of AP cells. Dual labeling for leptin proteins and growth hormone (GH) or gonadotropins showed that the rise in leptin protein-bearing cells from diestrus to proestrus was mainly in GH cells. Only 10-20% of leptin cells in male or cycling female rats coexpress gonadotropins. In contrast, 50-73% of leptin cells from pregnant or lactating females coexpress gonadotropins and only 19% coexpress GH, indicating plasticity in the distribution of leptin. Leptin cells expressed GnRH receptors, and estrogen and GnRH together increased the coexpression of leptin mRNA and gonadotropins. GnRH increased cellular leptin proteins three to four times and mRNA 9.8 times in proestrous rats and stimulated leptin secretion in cultures from diestrous, proestrous, and pregnant rats. These regulatory influences, and the high expression of AP leptin during proestrus and pregnancy, suggest a supportive role for leptin during key events involved with reproduction.

  4. Possible Integrative Actions of Leptin and Insulin Signaling in the Hypothalamus Targeting Energy Homeostasis

    PubMed Central

    Thon, Mina; Hosoi, Toru; Ozawa, Koichiro

    2016-01-01

    Obesity has emerged as one of the most burdensome conditions in modern society. In this context, understanding the mechanisms controlling food intake is critical. At present, the adipocyte-derived hormone leptin and the pancreatic β-cell-derived hormone insulin are considered the principal anorexigenic hormones. Although leptin and insulin signal transduction pathways are distinct, their regulation of body weight maintenance is concerted. Resistance to the central actions of leptin or insulin is linked to the emergence of obesity and diabetes mellitus. A growing body of evidence suggests a convergence of leptin and insulin intracellular signaling at the insulin–receptor–substrate–phosphatidylinositol-3-kinase level. Moreover, numerous factors mediating the pathophysiology of leptin resistance, a hallmark of obesity, such as endoplasmic reticulum stress, protein tyrosine phosphatase 1B, and suppressor of cytokine signaling 3 also contribute to insulin resistance. Recent studies have also indicated that insulin potentiates leptin-induced signaling. Thus, a greater understanding of the overlapping functions of leptin and insulin in the central nervous system is vital to understand the associated physiological and pathophysiological states. This mini-review focuses on the cross talk and integrative signaling of leptin and insulin in the regulation of energy homeostasis in the brain. PMID:27812350

  5. Skeletal bone morphology is resistant to the high amplitude seasonal leptin cycle in the Siberian hamster.

    PubMed

    Rousseau, K; Atcha, Z; Denton, J; Cagampang, F R A; Ennos, A R; Freemont, A J; Loudon, A S I

    2005-09-01

    Recent studies have suggested that the adipocyte-derived hormone, leptin, plays a role in the regulation of metabolism. Here, we tested this hypothesis in the seasonally breeding Siberian hamster, as this species exhibits profound seasonal changes in adiposity and circulating leptin concentrations driven by the annual photoperiodic cycle. Male hamsters were kept in either long (LD) or short (SD) photoperiods. Following exposure to short photoperiods for 8 weeks animals exhibited a significant weight-loss and a 16-fold reduction of serum leptin concentrations. At Week 9, animals in both photoperiods were infused with leptin or PBS via osmotic mini-pump for 14 days. Chronic leptin infusion mimicked LD-like concentrations in SD-housed animals and caused a further decline in body weight and adipose tissue. In LD-housed animals, leptin infusion resulted in a significant elevation of serum concentrations above natural LD-like levels, but had no discernable effect on body weight or overall adiposity. Both bending and compression characteristics and histomorphometric measurements of trabecular bone mass were unaltered by leptin treatment or photoperiod. Our data therefore show that despite a high natural amplitude cycle of leptin, this hormone has no apparent role in the regulation of bone metabolism, and therefore do not support recent propositions that this hormone is an important component in the metabolism of bone tissue.

  6. Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenic skinny mice overexpressing leptin.

    PubMed

    Ogawa, Yoshihiro; Masuzaki, Hiroaki; Ebihara, Ken; Shintani, Mitsuyo; Aizawa-Abe, Megumi; Miyanaga, Fumiko; Nakao, Kazuwa

    2002-01-01

    Leptin is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Plasma leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing leptin. They exhibit increased glucose metabolism and insulin sensitivity accompanied by a significant increase in insulin signaling for glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After caloric restriction, blood pressure elevation is reversed but insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma leptin concentrations. By contrast, blood pressure elevation is sustained but insulin resistance is reversed in transgenic mice overexpressing leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of leptin in obesity-related insulin resistance and hypertension.

  7. Effects of leptin on sympathetic nerve activity in conscious mice

    PubMed Central

    Morgan, Donald A; Despas, Fabien; Rahmouni, Kamal

    2015-01-01

    The adipocyte-derived hormone, leptin, has emerged as an important regulator of regional sympathetic nerve activity (SNA) with pathophysiological implications in obesity. Genetically engineered mice are useful to understand the molecular pathways underlying the SNA responses evoked by leptin. However, so far the effect of leptin on direct SNA in mice has been studied under general anesthesia. Here, we examined the sympathetic responses evoked by leptin in conscious mice. Mice were instrumented, under ketamine/xylazine anesthesia, with renal or lumbar SNA recordings using a thin (40 gauge) bipolar platinum–iridium wire. The electrodes were exteriorized at the nape of the neck and mice were allowed (5 h) to recover from anesthesia. Interestingly, the reflex increases in renal and lumbar SNA caused by sodium nitroprusside (SNP)-induced hypotension was higher in the conscious phase versus the anesthetized state, whereas the increase in both renal and lumbar SNA evoked by leptin did not differ between anesthetized or conscious mice. Next, we assessed whether isoflurane anesthesia would yield a better outcome. Again, the SNP-induced increase in renal SNA and baroreceptor-renal SNA reflex were significantly elevated in the conscious states relative to isoflurane-anesthetized phase, but the renal SNA response induced by leptin in the conscious states were qualitatively comparable to those evoked above. Thus, despite improvement in sympathetic reflexes in conscious mice the sympathetic responses evoked by leptin mimic those induced during anesthesia. PMID:26381017

  8. Effects of leptin on sympathetic nerve activity in conscious mice.

    PubMed

    Morgan, Donald A; Despas, Fabien; Rahmouni, Kamal

    2015-09-01

    The adipocyte-derived hormone, leptin, has emerged as an important regulator of regional sympathetic nerve activity (SNA) with pathophysiological implications in obesity. Genetically engineered mice are useful to understand the molecular pathways underlying the SNA responses evoked by leptin. However, so far the effect of leptin on direct SNA in mice has been studied under general anesthesia. Here, we examined the sympathetic responses evoked by leptin in conscious mice. Mice were instrumented, under ketamine/xylazine anesthesia, with renal or lumbar SNA recordings using a thin (40 gauge) bipolar platinum-iridium wire. The electrodes were exteriorized at the nape of the neck and mice were allowed (5 h) to recover from anesthesia. Interestingly, the reflex increases in renal and lumbar SNA caused by sodium nitroprusside (SNP)-induced hypotension was higher in the conscious phase versus the anesthetized state, whereas the increase in both renal and lumbar SNA evoked by leptin did not differ between anesthetized or conscious mice. Next, we assessed whether isoflurane anesthesia would yield a better outcome. Again, the SNP-induced increase in renal SNA and baroreceptor-renal SNA reflex were significantly elevated in the conscious states relative to isoflurane-anesthetized phase, but the renal SNA response induced by leptin in the conscious states were qualitatively comparable to those evoked above. Thus, despite improvement in sympathetic reflexes in conscious mice the sympathetic responses evoked by leptin mimic those induced during anesthesia.

  9. Leptin stimulates protein synthesis-activating translation machinery in human trophoblastic cells.

    PubMed

    Pérez-Pérez, Antonio; Maymó, Julieta; Gambino, Yésica; Dueñas, José L; Goberna, Raimundo; Varone, Cecilia; Sánchez-Margalet, Víctor

    2009-11-01

    Leptin was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in placenta, where it may work as an autocrine hormone, mediating angiogenesis, growth, and immunomodulation. Leptin receptor (LEPR, also known as Ob-R) shows sequence homology to members of the class I cytokine receptor (gp130) superfamily. In fact, leptin may function as a proinflammatory cytokine. We have previously found that leptin is a trophic and mitogenic factor for trophoblastic cells. In order to further investigate the mechanism by which leptin stimulates cell growth in JEG-3 cells and trophoblastic cells, we studied the phosphorylation state of different proteins of the initiation stage of translation and the total protein synthesis by [(3)H]leucine incorporation in JEG-3 cells. We have found that leptin dose-dependently stimulates the phosphorylation and activation of the translation initiation factor EIF4E as well as the phosphorylation of the EIF4E binding protein EIF4EBP1 (PHAS-I), which releases EIF4E to form active complexes. Moreover, leptin dose-dependently stimulates protein synthesis, and this effect can be partially prevented by blocking mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PIK3) pathways. In conclusion, leptin stimulates protein synthesis, at least in part activating the translation machinery, via the activation of MAPK and PIK3 pathways.

  10. Leptin and the hypothalamic-pituitary regulation of the gonadotropin-gonadal axis.

    PubMed

    Chan, J L; Mantzoros, C S

    2001-01-01

    Leptin is an adipocyte-derived protein hormone which not only conveys a signal of the amount of energy stores to the central nervous system but also plays an important role in regulating neuroendocrine function. The importance of leptin in the reproductive system has been suggested by the reproductive dysfunction associated with leptin deficiency and resistance in both animal models and humans as well as the ability of leptin to accelerate the onset of reproductive function in normal mice. Transgenic mice overexpressing leptin also have accelerated puberty, and leptin administration reverses the fasting-induced suppression of sexual maturation in rodents, indicating that leptin may serve as the critical link between sufficient energy stores and proper functioning of the reproductive system. Normal women have a pulsatile release pattern of leptin that is significantly associated with the variations in luteinizing hormone (LH) and estradiol levels. In various animal models, leptin administration restores the LH pulsatility pattern which is suppressed during fasting, indicating a hypothalamic site of action since LH pulsatility is under the control of gonadotropin-releasing hormone (GnRH). In humans, leptin has been administered to a 9-year-old leptin-deficient girl, resulting in a gonadotropin secretory pattern consistent with early puberty. While in vitro experiments with hypothalamic explants and a GnRH-secreting neuronal cell line have shown that leptin can directly stimulate GnRH secretion, the lack of leptin receptors on GnRH neurons suggests that leptin may act through other hypothalamic neuropeptides. Several neuropeptides which act as downstream effectors of leptin have been investigated, and recent studies indicate that cocaine and amphetamine-regulated transcript may be such a mediator of leptin's effect on GnRH. Leptin receptors have also been identified in human pituitaries, and leptin may influence LH release from the pituitary. However, the current

  11. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.

    PubMed

    Licinio, J; Negrão, A B; Mantzoros, C; Kaklamani, V; Wong, M L; Bongiorno, P B; Mulla, A; Cearnal, L; Veldhuis, J D; Flier, J S; McCann, S M; Gold, P W

    1998-03-01

    Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.

  12. Body composition, leptin, and the leptin receptor and their relationship to the growth hormone (GH) axis in growing wethers treated with zeranol.

    PubMed

    Narro, L A; Thomas, M G; Silver, G A; Rozeboom, K J; Keisler, D H

    2003-04-01

    Age-related changes in body composition, leptin, and hypothalamic-pituitary expression of the leptin receptor and associative relationships of these factors to constituents of the growth hormone (GH) axis were evaluated. Seventy wethers were randomly assigned at birth to one of four treatment groups: control; treatment 1 implanted with the estrogenic compound zeranol (12 mg, Ralgro on days 0, 45, and 90; treatment 2 received zeranol on days 45 and 90; and treatment 3 received zeranol on day 90. Serum and tissues were collected from wethers (n > or = 5) from each group on days 28, 73, 118, and 135. Percent body fat and leptin increased linearly (P < 0.01) with age, but were not influenced (P > or = 0.14) by zeranol. The leptin receptor in the pituitary appeared to be differentially (P = 0.097) expressed across days 73-135, but no differences (P > or = 0.43) were detected in expression of this receptor in the hypothalamus among treatments and ages. Leptin and % body fat were negatively correlated (r > or = -0.52, P < 0.05) to mRNA levels of factors involved in pituitary synthesis and secretion of GH. Serum leptin increased with age as did percent body fat, but zeranol did not influence body composition, serum leptin, or expression of the leptin receptor in the hypothalamus or pituitary; however, the leptin receptor appeared to be differentially expressed among the hypothalamus and pituitary with level of body fat and leptin being inversely associated to transcriptional-factors involved in somatotrope synthesis and secretion of GH.

  13. Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin.

    PubMed

    Yura, S; Ogawa, Y; Sagawa, N; Masuzaki, H; Itoh, H; Ebihara, K; Aizawa-Abe, M; Fujii, S; Nakao, K

    2000-03-01

    Excess or loss of body fat can be associated with infertility, suggesting that adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedly increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-deficient ob/ob mice. These findings suggest a role for leptin as an endocrine signal between fat depots and the reproductive axis, but the effect of hyperleptinemia on the initiation and maintenance of reproductive function has not been elucidated. To address this issue, we examined the reproductive phenotypes of female transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. With no apparent adipose tissue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterized by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonadotropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are associated with chronic hyperleptinemia, thereby leading to a better understanding of the pathophysiological and therapeutic implication of leptin.

  14. Leptin Responsive and GABAergic Projections to the Rostral Preoptic Area in Mice.

    PubMed

    Zuure, W A; Quennell, J H; Anderson, G M

    2016-03-01

    The adipocyte-derived hormone leptin plays a critical role in the control of reproduction via signalling in hypothalamic neurones. The drivers of the hypothalamic-pituitary-gonadal axis, the gonadotrophin-releasing hormone (GnRH) neurones, do not have the receptors for leptin. Therefore, intermediate leptin responsive neurones must provide leptin-to-GnRH signalling. We investigated the populations of leptin responsive neurones that provide input to the rostral preoptic area (rPOA) where GnRH cell bodies reside. Fluorescent retrograde tracer beads (RetroBeads; Lumafluor Inc., Naples, FL, USA) were injected into the rPOA of transgenic leptin receptor enhanced green fluorescent protein (Lepr-eGFP) reporter mice. Uptake of the RetroBeads by Lepr-eGFP neurones was assessed throughout the hypothalamus. RetroBead uptake was most evident in the medial arcuate nucleus (ARC), the dorsomedial nucleus (DMN) and the ventral premammillary nucleus (PMV) of the hypothalamus. The uptake of RetroBeads specifically by Lepr-eGFP neurones was highest in the medial ARC (18% of tracer-labelled neurones Lepr-eGFP-positive). Because neurones that are both leptin responsive and GABAergic play a critical role in the regulation of fertility by leptin, we next focussed on the location of these populations. To address whether GABAergic neurones in leptin-responsive hypothalamic regions project to the rPOA, the experiment was repeated in GABA neurone reporter mice (Vgat-tdTomato). Between 10% and 45% of RetroBead-labelled neurones in the ARC were GABAergic, whereas uptake of tracer by GABAergic neurones in the DMN and PMV was very low (< 5%). These results show that both leptin responsive and GABAergic neurones from the ARC project to the region of the GnRH cell bodies. Our findings suggest that LEPR-expressing GABA neurones from the ARC may be mediators of leptin-to-GnRH signalling.

  15. Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function.

    PubMed

    Zuure, Wieteke A; Roberts, Amy L; Quennell, Janette H; Anderson, Greg M

    2013-11-01

    The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.

  16. Serum Leptin and Loss of Control Eating in Children and Adolescents

    PubMed Central

    Miller, Rachel; Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Field, Sara E.; Hannallah, Louise; Reina, Samantha A.; Mooreville, Mira; Sedaka, Nicole; Brady, Sheila M.; Condarco, Tania; Reynolds, James C.; Yanovski, Susan Z.; Yanovski, Jack A.

    2014-01-01

    Background Both insufficiency and resistance to the actions of the adipocyte-derived hormone leptin promote hunger, increased food intake, and greater body weight. Some studies suggest adults reporting binge eating have increased serum leptin compared to those without binge eating, even after adjusting for the greater adiposity that characterizes binge eaters. Pediatric binge or loss of control (LOC) eating are prospective risk factors for excessive weight gain and may predict development of metabolic abnormalities, but whether LOC eating is associated with higher leptin among children is unknown. We therefore examined leptin and LOC eating in a pediatric cohort. Methods A convenience sample of 506 lean and obese youth (7–18y) was recruited from Washington, DC and its suburbs. Serum leptin was collected after an overnight fast. Adiposity was measured by dual-energy x-ray absorptiometry or air displacement plethysmography. LOC eating was assessed by interview methodology. Results Leptin was strongly associated with fat mass (r=.79, p<.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared to those without LOC episodes (15.42±1.05 vs. 12.36±1.04 ng/mL, p<.001). Neither reported amount of food consumed during a recent LOC episode nor number of LOC episodes in the previous month accounted for differences in leptin (ps>.05). The relationship between LOC eating and leptin appeared to be significant for females only (p=0.002). Conclusions Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate if LOC eating promotes greater leptin or if greater leptin resistance may promote LOC eating. PMID:23835660

  17. Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression.

    PubMed

    Gambino, Y P; Maymó, J L; Pérez Pérez, A; Calvo, J C; Sánchez-Margalet, V; Varone, C L

    2012-02-01

    The steroid hormone 17β-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane-associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression.

  18. The effect of leptin on Na(+)-H(+) antiport (NHE 1) activity of obese and normal subjects erythrocytes.

    PubMed

    Konstantinou-Tegou, A; Kaloyianni, M; Bourikas, D; Koliakos, G

    2001-10-25

    Obesity is currently considered as a chronic metabolic disease, associated with a high risk of cardiovascular complications. Leptin, an adipocyte-derived hormone has a variety target cells influencing a wide range of processes. Possible counteractions of hyperleptinaemia are currently investigated. The Na(+)-H(+) exchanger (NHE 1) is involved in multiple cellular functions and its activation has been related to hypertension and obesity. NHE 1 is present on erythrocytes and can be stimulated by various hormones. Erythrocytes have on their surface a variety of receptors with mostly unknown function. In the present paper, the effect of leptin on erythrocytes NHE 1 activity has been investigated. For this reason, the intracellular pH and sodium influxes were measured before and after addition of leptin in erythrocyte suspensions from normal and obese individuals. Amiloride, a specific NHE 1 inhibitor, and staurosporine a protein kinase C inhibitor were used to inhibit erythrocyte NHE 1. For the binding study leptin was labeled with fluorescein isothiocyanate (FITC) and the binding on erythrocytes was estimated by Scatchard analysis. NHE 1 activity increased in the presence of leptin but significantly less in the obese than in the control group. Furthermore the concentrations of leptin binding sites on the surface of erythrocytes were lower in erythrocytes drawn from obese individuals than in erythrocytes drawn from normal subjects. Since NHE 1 activity has been associated with insulin resistance and hypertension, the activation of this antiport by leptin may represent a link between adipose tissue hypertrophy and cardiovascular complications of obesity.

  19. Insulin enhanced leptin-induced STAT3 signaling by inducing GRP78

    PubMed Central

    Thon, Mina; Hosoi, Toru; Ozawa, Koichiro

    2016-01-01

    Leptin, an adipocyte-derived hormone, centrally regulates energy homeostasis. Overlaps in the regulation of glucose and energy homeostasis have been reported between leptin and insulin. However, the effects of insulin on leptin’s actions in the central nervous system (CNS) have not yet been elucidated in detail. In the present study, we found that insulin potentiated leptin’s actions through GRP78 in the neuronal cell line, SH-SY5Y-ObRb. Since insulin induces GRP78, we speculated that it may also enhance leptin’s actions through this induction. We found that insulin enhanced leptin-induced STAT3 phosphorylation and this effect was ameliorated by the knockdown of GRP78. The role of GRP78 in leptin’s actions was also confirmed by impairments in leptin-induced STAT3 phosphorylation in HEK293-ObRb cells in which GRP78 was knocked down. Furthermore, we found that the overexpression of GRP78 enhanced leptin-induced STAT3 phosphorylation. These results suggest that GRP78 plays an important role in leptin’s actions. Furthermore, insulin may enhance the leptin-induced activation of STAT3 by inducing GRP78, which may provide an important connection between insulin and leptin in the CNS. PMID:27677243

  20. Plasma concentration of total leptin and human lung-cancer-associated cachexia.

    PubMed

    Simons, J P; Schols, A M; Campfield, L A; Wouters, E F; Saris, W H

    1997-09-01

    1. Adipocyte-derived leptin is postulated to represent the afferent hormonal signal to the hypothalamus in a feedback mechanism that regulates fat mass. In this proposed feedback mechanism, increased fat mass leads to an elevated plasma leptin level that eventually induces a decrease in appetite and an increase in energy expenditure, and vice versa. 2. As anorexia and hypermetabolism play a role in the development of cancer cachexia, we investigated the hypothesis that underlying abnormalities in the leptin feedback mechanism (in particular relatively high plasma leptin levels or, on the other hand, a hypothalamic insensitivity to a fall in leptin levels) might be involved. For this purpose, total plasma leptin, body composition (fat mass and fat-free mass), appetite and resting energy expenditure were assessed in 21 male lung-cancer patients. 3. Total leptin was detectable in six patients and non-detectable in 15. In comparison with the latter, the patients with detectable leptin were characterized by a trend towards less weight loss (3.4% compared with 11.0%, P = 0.07), as being less underweight (body mass index 23.8 kg/m2 compared with 19.4 kg/m2, P = 0.004) and by a higher fat mass (21.4 kg compared with 9.7 kg, P = 0.001). Significant between-group differences in appetite and resting energy expenditure were lacking. 4. Based on these findings, we conclude that in cancer the afferent part of the leptin feedback mechanism functions normally and that, in particular, elevated leptin levels are not involved in the development of cachexia. Since the absence of plasma leptin was not associated with an increased appetite and decreased energy expenditure, disturbances in the hypothalamic part of the feedback mechanism are hypothesized. PMID:9337643

  1. Expression of functional leptin receptors in rodent Leydig cells.

    PubMed

    Caprio, M; Isidori, A M; Carta, A R; Moretti, C; Dufau, M L; Fabbri, A

    1999-11-01

    Several studies indicate that the size of body fat stores and the circulating levels of the adipocyte-derived hormone leptin are able to influence the activity of the hypothalamic-pituitary-gonadal axis. The leptin-hypothalamic-pituitary-gonadal interactions have been mainly studied at the level of the central nervous system. In this study, we investigated the possibility that leptin may have direct effects on the rodent Leydig cell function. To probe this hypothesis, we first analyzed the expression of leptin receptors (OB-R) in rodent Leydig cells in culture. RT-PCR studies showed that rat Leydig cells express both the long (OB-Rb) and short isoform (OB-Ra) of leptin receptor, whereas MLTC-1 cells (a murine Leydig tumor cell line) express only the long isoform. Short-term (30-90 min) incubation of rat Leydig cells with increasing concentrations ofleptin (2-500 ng/ml) led to a significant and dose-dependent inhibition of human (h)CG-stimulated testosterone (T) production (approximately 60% reduction, IC50 = 20 ng/ml) but no change in basal androgen release. Also, leptin (150 ng/ml) amplified hCG-induced intracellular cAMP formation (1- to 2-fold) without modifying basal cAMP levels. Subsequent experiments showed that leptin inhibited 8Br-cAMP-stimulated T production, indicating that leptin's effect is exerted beyond cAMP. The inhibitory effect of leptin on hCG-induced T secretion was accompanied by a significant reduction of androstenedione and a concomitant rise of the precursor metabolites pregnenolone, progesterone, and 17-OH-progesterone, conceivable with a leptin-induced lesion of 17,20 lyase activity. Separate experiments performed with the MLTC-1 cells (not expressing cytochrome P450-17alpha) showed that leptin, though amplifying hCG-stimulated cAMP production, did not modify hCG-stimulated pregnenolone and progesterone release. These results further indicate that leptin action on steroidogenesis occurs downstream of progesterone synthesis. Northern Blot

  2. Differential Role of Leptin as an Immunomodulator in Controlling Visceral Leishmaniasis in Normal and Leptin-Deficient Mice

    PubMed Central

    Maurya, Radheshyam; Bhattacharya, Parna; Ismail, Nevien; Dagur, Pradeep K.; Joshi, Amritanshu B.; Razdan, Kundan; McCoy, J. Philip; Ascher, Jill; Dey, Ranadhir; Nakhasi, Hira L.

    2016-01-01

    Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani. There are no vaccines and available drugs against leishmaniasis are toxic. Immunomodulators that specifically boost the anti-microbial activities of the immune cells could alleviate several of these limitations. Therefore, finding novel immunomodulators for VL therapy is a pressing need. This study is aimed to evaluate the immunomodulatory role of leptin, an adipocyte-derived hormone capable of regulating the immune response, in L. donovani-infected mice. We observed that recombinant leptin treatment reduced splenic parasite burden compared with non-treated infected normal mice. Decrease in parasite burden correlated with an induction of innate immune response in antigen-presenting cells that showed an increase in nitric oxide, enhanced pro-inflammatory cytokine (interferon gamma [IFNγ], interleukin12 [IL]12, and IL1β) response in the splenocytes, indicating host-protecting Th1 response mediated by leptin. Moreover, in infected normal mice, leptin treatment induced IFNγ production from both CD4+ and CD8+ T cells, compared with non-treated infected mice. Alternatively, leptin-deficient (Ob/Ob) mice had higher splenic and liver parasite burden compared with the infected normal mice. However, leptin treatment failed to reduce the splenic parasite burden and improve a host-protective cytokine response in these mice. In addition, in contrast to dendritic cells (DCs) from a normal mouse, Ob/Ob mouse–derived DCs showed a defect in the induction of innate immune response on Leishmania infection that could not be reversed by leptin treatment. Therefore, our findings reveal that leptin has a differential immunomodulatory effect in controlling VL in normal and Ob/Ob mice. PMID:27114296

  3. Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome.

    PubMed

    Mantzoros, C S; Cramer, D W; Liberman, R F; Barbieri, R L

    2000-03-01

    Leptin is an adipocyte-derived hormone which plays a central role in the regulation of body weight and energy homeostasis and in signalling to the brain that adequate energy stores are available for reproduction. Although leptin may affect reproduction by regulating the hypothalamic-pituitary-gonadal axis, recent in-vitro observations indicate that leptin may also have direct intra-ovarian actions. Leptin concentrations were measured in women who succeeded in becoming pregnant within three cycles of in-vitro fertilization (IVF) or gamete intra-fallopian transfer (n = 53), in women who failed to become pregnant within three cycles (n = 50), and in women with polycystic ovarian syndrome (PCOS) (n = 22). It was found that lower follicular fluid leptin concentrations were a marker of assisted reproduction treatment success in normal women. Women with PCOS had higher leptin concentrations than women without such a diagnosis, but this was due to their higher body mass index (BMI). After adjustment for age and BMI, women with PCOS who became pregnant tended to have lower mean follicular fluid leptin concentrations than women with PCOS who did not succeed at becoming pregnant. Further studies exploiting the strengths of the IVF model are needed to assess whether the prognostic role for follicular fluid leptin in human reproduction is independent of other factors, and to elucidate the underlying mechanisms.

  4. Hormonal modulation of food intake in response to low leptin levels induced by hypergravity

    NASA Technical Reports Server (NTRS)

    Moran, M. M.; Stein, T. P.; Wade, C. E.

    2001-01-01

    A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.

  5. Hormonal modulation of food intake in response to low leptin levels induced by hypergravity.

    PubMed

    Moran, M M; Stein, T P; Wade, C E

    2001-09-01

    A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.

  6. Resting metabolic rate in healthy adults: relation to growth hormone status and leptin levels.

    PubMed

    Jørgensen, J O; Vahl, N; Dall, R; Christiansen, J S

    1998-09-01

    Studies in patients with acromegaly and growth hormone (GH) deficiency, and administration of GH in normal and obese subjects and in patients with GH deficiency, suggest that GH increases resting metabolic rate (RMR) independently of changes in body composition. To test whether endogenous GH status determines RMR, we studied 38 healthy adults (18 women and 18 men) in two age groups (young, 30+/-0 years (n=18); older, 51+/-1 years [n=18]) with indirect calorimetry, deconvolution analysis of 24-hour GH secretion, arginin stimulation test, insulin-like growth factor-I (IGF-I) measurement, lean and fat tissue distribution (computed tomography [CT] and dual-energy x-ray absorptiometry), assessment of physical fitness (maximal oxygen consumption [VO2max]), thyroid status, and serum leptin levels. RMR was higher in men compared with women, whereas RMR per lean body mass (LBM) (kcal x 24 h(-1) x kg(-1)) was higher in women (30.0+/-0.5 v 33.0 2/3 0.8; P=.003). GH secretion was higher in women and in young people. Total-body fat (TBF) was higher in women, whereas LBM and abdominal fat were higher in men. Older people had significantly more TBF and abdominal fat as compared with younger people. VO2max was higher in younger people. Leptin levels were higher in women and in older people. Thyroid status was narrowly within the normal range in all subjects. RMR was strongly correlated with LBM (r=.90, P < .001). RMR/LBM correlated strongly with TBF (r=.49, P < .01) and leptin (r=.56, P < .001), but not with GH status. By multiple regression analysis, sex and TBF were the strongest predictors of RMR/LBM. However, in the young subgroup, GH production rate was a positive determinant of RMR/LBM. In the male subgroup, leptin was a stronger predictor than TBF of RMR/LBM (P < .001). Neither age, physical fitness, nor thyroid status contributed independently to predict RMR/LBM. In conclusion, (1) LBM was the most important determinant of RMR; (2) RMR/LBM was higher in women and depended

  7. Site-specific (18)F-labeling of the protein hormone leptin using a general two-step ligation procedure.

    PubMed

    Flavell, Robert R; Kothari, Paresh; Bar-Dagan, Maya; Synan, Michael; Vallabhajosula, Shankar; Friedman, Jeffrey M; Muir, Tom W; Ceccarini, Giovanni

    2008-07-16

    The protein hormone leptin acts to regulate body fat and energy expenditure. Resistance to this hormone is implicated in human obesity and its pathophysiological consequences. In order to gain insight into the mechanism of leptin resistance, an (18)F-labeled derivative was developed to study the biodistribution of the hormone using positron emission tomography (PET). A two-step, site specific ligation approach was developed for this purpose, in which an aminooxy-reactive group was incorporated at the C-terminus of leptin using expressed protein ligation (EPL), which was subsequently derivatized with [ (18)F]fluorobenzaldehyde using an aniline-accelerated radiochemical oximation reaction. The modified hormone was shown to be biologically active in vitro and in vivo, and it was applied to PET imaging in ob/ ob mice. These protocols will allow for the routine production of site-specifically (18)F radiolabeled leptin, as well as other proteins, for use in PET imaging in systems from mouse to man.

  8. Leptin induces macrophage lipid body formation by a phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent mechanism.

    PubMed

    Maya-Monteiro, Clarissa M; Almeida, Patricia E; D'Avila, Heloisa; Martins, Aline S; Rezende, Ana Paula; Castro-Faria-Neto, Hugo; Bozza, Patricia T

    2008-01-25

    Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Lipid bodies (lipid droplets) are emerging as dynamic organelles with roles in lipid metabolism and inflammation. Here we investigated the roles of leptin in signaling pathways involved in cytoplasmic lipid body biogenesis and leukotriene B(4) synthesis in macrophages. Our results demonstrated that leptin directly activated macrophages and induced the formation of adipose differentiation-related protein-enriched lipid bodies. Newly formed lipid bodies were sites of 5-lipoxygenase localization and correlated with an enhanced capacity of leukotriene B(4) production. We demonstrated that leptin-induced macrophage activation was dependent on phosphatidylinositol 3-kinase (PI3K) activity, since the lipid body formation was inhibited by LY294002 and was absent in the PI3K knock-out mice. Leptin induces phosphorylation of p70(S6K) and 4EBP1 key downstream signaling intermediates of the mammalian target of rapamycin (mTOR) pathway in a rapamycin-sensitive mechanism. The mTOR inhibitor, rapamycin, inhibited leptin-induced lipid body formation, both in vivo and in vitro. In addition, rapamycin inhibited leptin-induced adipose differentiation-related protein accumulation in macrophages and lipid body-dependent leukotriene synthesis, demonstrating a key role for mTOR in lipid body biogenesis and function. Our results establish PI3K/mTOR as an important signaling pathway for leptin-induced cytoplasmic lipid body biogenesis and adipose differentiation-related protein accumulation. Furthermore, we demonstrate a previously unrecognized link between intracellular (mTOR) and systemic (leptin) nutrient sensors in macrophage lipid metabolism. Leptin-induced increased formation of cytoplasmic lipid bodies and enhanced inflammatory mediator production in macrophages may have implications for obesity-related cardiovascular diseases. PMID:18039669

  9. Serum leptin measured in early pregnancy is higher in women with preeclampsia compared with normotensive pregnant women.

    PubMed

    Taylor, Brandie D; Ness, Roberta B; Olsen, Jørn; Hougaard, David M; Skogstrand, Kristin; Roberts, James M; Haggerty, Catherine L

    2015-03-01

    Leptin, an adipocyte-derived hormone, plays an important role in reproduction and angiogenesis. Studies examining leptin in preeclampsia are inconsistent, possibly because of small sample sizes and variability in sampling and outcome. We conducted a nested case-control study to examine associations between serum leptin (measured: 9-26 weeks gestation) and preeclampsia among 430 primiparous preeclamptic women and 316 primiparous normotensive controls from the Danish National Birth Cohort. Median (interquartile range) leptin concentrations were calculated. Associations between leptin and preeclampsia (blood pressure ≥140/90 mm Hg), term preeclampsia (preeclampsia and delivery ≥37 weeks gestation), or preterm preeclampsia (preeclampsia and delivery <37 weeks gestation) were examined using generalized linear models adjusting for body mass index, gestational age at blood draw, maternal age, smoking, and socio-occupational status. As leptin is increased in obese women and the risk of preeclampsia increases with body mass index, we used the Sobel test to examine whether leptin is a mediator of this relationship. After adjustments, leptin concentrations were significantly higher in women with preeclampsia (30.5 [24.6]; P=0.0117) and term preeclampsia (30.4 [24.9]; P=0.0228) compared with controls (20.9 [28.3]). There was no significant difference between preterm preeclampsia (30.6 [23.4]; P=0.2210) and controls. Leptin is a possible mediator of the association between body mass index and preeclampsia (P=0.0276). Leptin concentrations are higher in women with preeclampsia compared with normotensive controls and may mediate some of the relationship between body mass index and preeclampsia.

  10. Roles of ghrelin and leptin in the control of reproductive function.

    PubMed

    Tena-Sempere, Manuel

    2007-01-01

    Reproductive function in mammals, defined as the capacity to generate viable male and female gametes, and to support pregnancy and lactation selectively in the female, is sensitive to the metabolic state of the organism. This contention, long assumed on the basis of intuitive knowledge, became formulated on a scientific basis only recently, with the identification of a number of neuroendocrine signals which crucially participate in the joint control of energy balance and reproduction. A paradigmatic example in this context is the adipocyte-derived hormone, leptin; a satiety factor which signals the amount of body energy (fat) stores not only to the circuits controlling food intake but also to a number of neuroendocrine axes, including the reproductive system. More recently, the reproductive dimension of another metabolic hormone, namely the orexigenic stomach-secreted peptide, ghrelin, has been disclosed by observations on its putative roles in the control of gonadal function and gonadotropin secretion. Of note, leptin and ghrelin have been proposed to act as reciprocal regulators of energy homeostasis. However, their potential interplay in the control of reproduction remains largely unexplored. Based on the comparison of the biological actions of leptin and ghrelin at different levels of the hypothalamic-pituitary-gonadal axis, reviewed in detail herein, we propose that, through concurrent or antagonistic actions, the leptin-ghrelin pair is likely to operate also as modulator of different reproductive functions, thereby contributing to the physiological integration of reproduction and energy balance.

  11. Ghrelin and its interactions with growth hormone, leptin and orexins: implications for the sleep-wake cycle and metabolism.

    PubMed

    García-García, Fabio; Juárez-Aguilar, Enrique; Santiago-García, Juan; Cardinali, Daniel P

    2014-02-01

    Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep-wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern.

  12. Interrelationship between feeding level and the metabolic hormones leptin, ghrelin and obestatin in control of chicken egg laying and release of ovarian hormones.

    PubMed

    Sirotkin, Alexander V; Grossmann, Roland

    2015-06-01

    The aim of the present experiment is to examine the role of nutritional status, metabolic hormones and their interrelationships in the control of chicken ovarian ovulatory and secretory activity. For this purpose, we identified the effect of food restriction, administration of leptin, ghrelin 1-18, obestatin and combinations of food restriction with these hormones for 3days on chicken ovulation (egg laying) rate and ovarian hormone release. The release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) by isolated and cultured ovarian fragments was determined by EIA. It was observed that food restriction significantly reduced the egg-laying rate, T, E and AVT release and promoted P output by ovarian fragments. Leptin, administrated to ad libitum-fed chickens, did not change these parameters besides promoting E release. Nevertheless, administration of leptin was able to prevent the effect of food restriction on ovulation, T and E (but not P or AVT) release. Ghrelin 1-18 administration to ad libitum-fed birds did not affect the measured parameters besides a reduction in P release. Ghrelin 1-18 administration prevented the food restriction-induced decrease in ovarian T, E and AVT, but it did not change P output or egg laying. Obestatin administrated to control chicken promoted their ovarian P, E and inhibited ovarian AVT release but did not affect egg laying. It was able to promote the effect of food restriction on P, T and AVT, but not E release or egg laying. Our results (1) confirm an inhibitory effect of food restriction on chicken ovulation rate; (2) shows that food restriction-induced reduction in egg laying is associated with a decrease in ovarian T, E and AVT and an increase in ovarian P release; (3) confirm the involvement of metabolic hormones leptin, ghrelin and obestatin in the control of chicken ovarian hormones output; and (4) the ability of metabolic hormones to mimic/antagonize or prevent/promote the effects of food

  13. Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation.

    PubMed

    Xue, Baojian; Yu, Yang; Zhang, Zhongming; Guo, Fang; Beltz, Terry G; Thunhorst, Robert L; Felder, Robert B; Johnson, Alan Kim

    2016-05-01

    Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

  14. Negative Regulation of Leptin-induced Reactive Oxygen Species (ROS) Formation by Cannabinoid CB1 Receptor Activation in Hypothalamic Neurons.

    PubMed

    Palomba, Letizia; Silvestri, Cristoforo; Imperatore, Roberta; Morello, Giovanna; Piscitelli, Fabiana; Martella, Andrea; Cristino, Luigia; Di Marzo, Vincenzo

    2015-05-29

    The adipocyte-derived, anorectic hormone leptin was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of reactive oxygen species (ROS) levels in arcuate nucleus (ARC) neurons. Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity. Here we investigated the possibility of a negative regulation by CB1 receptors of leptin-mediated ROS formation in the ARC. Through pharmacological and molecular biology experiments we report data showing that leptin-induced ROS accumulation is 1) blunted by arachidonyl-2'-chloroethylamide (ACEA) in a CB1-dependent manner in both the mouse hypothalamic cell line mHypoE-N41 and ARC neuron primary cultures, 2) likewise blocked by a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, troglitazone, in a manner inhibited by T0070907, a PPAR-γ antagonist that also inhibited the ACEA effect on leptin, 3) blunted under conditions of increased endocannabinoid tone due to either pharmacological or genetic inhibition of endocannabinoid degradation in mHypoE-N41 and primary ARC neuronal cultures from MAGL(-/-) mice, respectively, and 4) associated with reduction of both PPAR-γ and catalase activity, which are reversed by both ACEA and troglitazone. We conclude that CB1 activation reverses leptin-induced ROS formation and hence possibly some of the ROS-mediated effects of the hormone by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity. This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels.

  15. Gut hormones and leptin: impact on energy control and changes after bariatric surgery--what the future holds.

    PubMed

    Michalakis, Konstantinos; le Roux, Carel

    2012-10-01

    Obesity is now considered the new world epidemic. In an attempt to face this menace to public health, several treatments, apart from the traditional nutritional modification and oral medication, have been introduced, among them bariatric surgery and gut hormone-based treatments. The gastrointestinal (GI) tract is a powerful endocrine organ, releasing active peptides and influencing appetite and glycaemic control. Alteration of the GI tract, in ways that exaggerate the secretion and levels of the gut hormones, creates a new functional equilibrium that further contributes to weight loss. The purpose of this review is to explore the mechanisms that drive this gut hormone-derived body regulation, as well as the changes that occur to them after bariatric surgery. Close to that, leptin, a hormone secreted by adipose tissue will be analysed, as its pathways are closely related to those of the gut hormones. Gut hormones are strongly implicated in energy control, and various effects of bariatric surgery in weight loss are directly related to the alteration of the levels of these hormones. PMID:22692670

  16. Hormone and metabolic factors associated with leptin mRNA expression in pre- and postmenopausal women.

    PubMed

    Fajardo, Martha E; Malacara, Juan M; Martínez-Rodríguez, Herminia G; Barrera-Saldaña, Hugo A

    2004-06-01

    Recent information has extended leptin's action, beyond the control of appetite, to various sites of metabolic regulation. To better understand leptin's role we studied its production in subcutaneous and visceral fat compartments before and after menopause. During elective abdominal surgery, biopsies of subcutaneous and omental tissues were taken from 20 women at pre- (BMI 28.4 +/- 4.5 kg/m2) and 10 at postmenopause (BMI 30.6 +/- 7.7 kg/m2). In both groups serum leptin levels were similar, and highly correlated with BMI. In subcutaneous adipose tissue, leptin mRNA expression was significantly higher in pre- than in postmenopausal women (50.4 +/- 20.5 amol/microg total RNA versus 34.5 +/- 24.9 amol/microg total RNA, respectively). Leptin mRNA expression in subcutaneous tissue was independently correlated with fasting glucose (R = 0.89, P < 0.006) at premenopause, and with serum estradiol (R = 0.77, P < 0.04) at postmenopause. Leptin mRNA expression in visceral fat was correlated with DHEAS (R = 0.86, P < 0.001), at premenopause. These results indicate that in both compartments, leptin production is sensitive to different but overlapping stimuli, conveying information about energy availability to central and peripheral sites under different conditions of estrogen exposure.

  17. Effects of dietary energy and protein density on plasma concentrations of leptin and metabolic hormones in dairy heifers.

    PubMed

    Chelikani, P K; Ambrose, D J; Keisler, D H; Kennelly, J J

    2009-04-01

    The hormonal and metabolic signals that communicate the level of body energy reserves to the reproductive-mammary axis remain undefined in dairy cattle; consequently, our hypothesis was that leptin may fulfill this role. Our objectives were to determine the effects of diets differing in energy and protein density on dry matter intake (DMI), growth traits [body weight (BW), body condition score (BCS), back-fat (BF) thickness], and temporal changes in plasma concentrations of leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, and nonesterified fatty acids (NEFA) in dairy heifers during the pre- and postpubertal periods. In period 1, heifers were randomly allotted (n = 10/diet) at 103 kg of BW to diets for a predicted average daily gain of 1.10 (high, H), 0.80 (medium, M), or 0.50 kg/d (low, L). Five heifers in each of the H and L groups were further studied during period 2, either at 12 mo of age (HA, LA) or at 330 kg of BW (HW, LW). The data provide evidence that 1) DMI (18%), BW (17%), and BF (5%) together explained 40% of the variation in plasma leptin concentrations (r(2) = 0.396); 2) unlike the acute postprandial increase in plasma insulin as a result of increased nutrient density (H 1.42 +/- 0.09, M 1.02 +/- 0.09, L 0.68 +/- 0.11 ng/mL), plasma leptin concentrations did not respond acutely with a distinct postprandial profile; 3) although plasma leptin concentrations increased with age, leptin at puberty did not differ among treatment groups (H 5.63 +/- 2.48, M 4.28 +/- 0.55, L 4.12 +/- 0.72 ng/mL) and there was no evidence of an abrupt transition in prepubertal plasma leptin concentrations; 4) plasma leptin concentrations may not be a critical trigger for puberty in rapidly growing heifers, but are apparently essential for puberty in heifers with normal or restricted growth rates; and 5) plasma concentrations of insulin (H 0.59 +/- 0.07, M 0.43 +/- 0.09, L 0.30 +/- 0.09 ng/mL), IGF-1 (H 151.08 +/- 16.47, L 82.51 +/- 17.47 ng

  18. Leptin and adiponectin levels in middle-aged postmenopausal women: associations with lifestyle habits, hormones, and inflammatory markers--a cross-sectional study.

    PubMed

    Rolland, Yves M; Perry, Horace M; Patrick, Ping; Banks, William A; Morley, John E

    2006-12-01

    To investigate the relationships between blood levels of leptin or adiponectin and lifestyle habits, hormones, and inflammatory markers, we measured parameters of alcohol intake, smoking, physical activity, and blood levels of leptin, adiponectin, testosterone, estrone, estradiol, cortisol, dihydroepiandrostenedione, luteinizing hormone, thyroxin, C-reactive protein (CRP), and interleukin 6 and interleukin 2 receptor in 76 healthy middle-aged postmenopausal women. Anthropometric measures and body composition (evaluated by dual-energy x-ray absorptiometry) and lipid profiles were also assessed. By simple regression, leptin correlated positively with fat and lean masses, glucose, triglycerides, low-density lipoprotein cholesterol, and total cholesterol, and negatively with high-density lipoprotein cholesterol. Adioponectin correlated negatively with fat and lean masses and low-density lipoprotein cholesterol, and positively with high-density lipoprotein cholesterol. Leptin concentration was correlated inversely with adiponectin (r = -0.26, P < .05) and positively with CRP (r = 0.56, P < .01). Adiponectin concentration was negatively correlated with time since last alcoholic drink (r = -0.24, P < .05) and CRP (r = -0.27, P < .05) and positively with testosterone level (r = 0.23, P < .05). By multiple regression analysis, leptin concentration was predicted by age (P < .05), testosterone (P < .05), adiponectin (P < .05), CRP (P < .01), and interleukin 6 receptor (P < .01). Adiponectin concentration was predicted by the time since last alcoholic drink (P < .05), testosterone (P < .05), leptin (P < .05), and C-reactive protein (P = .05). Similar results were found when leptin or adiponectin concentration was adjusted for fat mass. These results suggested that levels of leptin and adiponectin in middle-aged postmenopausal women are partially determined by sexual hormones and inflammatory marker levels, and both predicted one another. Moreover, adiponectin level may be

  19. Effect of fat supplementation on leptin, insulin-like growth factor I, growth hormone, and insulin in cattle

    PubMed Central

    Becú-Villalobos, Damasia; García-Tornadú, Isabel; Shroeder, Guillermo; Salado, Eloy E.; Gagliostro, Gerardo; Delavaud, Carole; Chilliard, Yves; Lacau-Mengido, Isabel M.

    2007-01-01

    We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models. PMID:17695598

  20. Leptin: a novel therapeutic strategy for Alzheimer's disease.

    PubMed

    Tezapsidis, Nikolaos; Johnston, Jane M; Smith, Mark A; Ashford, J Wesson; Casadesus, Gemma; Robakis, Nikolaos K; Wolozin, Benjamin; Perry, George; Zhu, Xiongwei; Greco, Steven J; Sarkar, Sraboni

    2009-01-01

    Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients. PMID:19387109

  1. Leptin-Responsive GABAergic Neurons Regulate Fertility through Pathways That Result in Reduced Kisspeptinergic Tone

    PubMed Central

    Martin, Cecilia; Navarro, Víctor M.; Simavli, Serap; Vong, Linh; Carroll, Rona S.; Lowell, Bradford B.

    2014-01-01

    The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Leprlox/lox and Vglut2-Cre;Leprlox/lox mice, respectively. Female Vgat-Cre;Leprlox/lox but not Vglut2-Cre;Leprlox/lox mice were obese. Vgat-Cre;Leprlox/lox mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Leprlox/lox females exhibited reproductive maturation and function comparable to Leprlox/lox control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Leprlox/lox female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Leprlox/lox mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Leprlox/lox mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons. PMID:24760864

  2. Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression.

    PubMed

    Guo, Ming; Lu, Yuan; Garza, Jacob C; Li, Yuqing; Chua, Streamson C; Zhang, Wei; Lu, Bai; Lu, Xin-Yun

    2012-01-01

    The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates NMDA-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the GluN2B subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestations of depression.

  3. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin.

    PubMed

    Nagy, G Sonia; Tsiodras, Sotirios; Martin, Lizabeth D; Avihingsanon, Anchalee; Gavrila, Alina; Hsu, William C; Karchmer, Adolf W; Mantzoros, Christos S

    2003-03-15

    The relationship between the adipocyte-derived hormone leptin, insulin resistance, and fat redistribution in patients with human immunodeficiency virus (HIV) infection has not been established. We classified a cohort of HIV type 1 (HIV-1)-infected patients with >or=6 months of antiretroviral exposure as having no lipodystrophy (51 patients [43% of the cohort]), lipoatrophy (23 patients [19% of the cohort]), mixed lipodystrophy (29 patients [24% of the cohort]), or lipohypertrophy (17 patients [14% of the cohort]), on the basis of physical examination, anthropometric measurements, and the findings of dual-emission x-ray absorptiometry and computed tomography. Measurements of insulin resistance were higher for patients with each category of lipodystrophy, compared with those observed for patients with no lipodystrophy (P<.001). Mean leptin levels (+/- standard deviation) were lowest in patients with lipoatrophy (1.76+/-1.20 ng/mL), highest in patients with lipohypertrophy (9.10+/-6.86 ng/mL), and significantly different from those in patients without lipodystrophy (3.14+/-2.30 ng/mL; both P<.01). In this cohort of antiretroviral-experienced HIV-infected patients, a low serum level of leptin was independently associated with insulin resistance in patients with lipoatrophy, after controlling for total and regional body fat.

  4. Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin.

    PubMed

    Somogyi, V; Gyorffy, A; Scalise, T J; Kiss, D S; Goszleth, G; Bartha, T; Frenyo, V L; Zsarnovszky, A

    2011-06-01

    Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

  5. Hormone Resistance in Diabetes and Obesity: Insulin, Leptin, and FGF21

    PubMed Central

    Flier, Jeffrey S.

    2012-01-01

    This an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife’s research on insulin, leptin, and FGF21 in the context of his reflections upon his life’s work and his advice for young investigators. PMID:23012588

  6. Profile of leptin, adiponectin, and body fat in patients with hyperprolactinemia: Response to treatment with cabergoline

    PubMed Central

    Pala, Nazir Ahmad; Laway, Bashir Ahmad; Misgar, Raiz Ahmad; Shah, Zaffar Amin; Gojwari, Tariq A.; Dar, Tariq A.

    2016-01-01

    Introduction: Though hypoadiponectinemia and leptin resistance have been proposed as potential factors for weight gain in patients with hyperprolactinemia (HPL), the effects of HPL and cabergoline on these adipocyte-derived hormones are not clear. Aims of this study were (i) to assess the alterations of body fat, leptin, and adiponectin in patients with HPL (ii) effect of cabergoline treatment on these parameters. Methods: Nineteen consecutive patients with prolactinoma (median prolactin [PRL] 118.6 (interquartile range: 105.3) μg/L) and 20 controls were studied in a nonrandomized matched prospective design. The controls were age, gender, and body mass index (BMI) matched. Anthropometric data, metabolic variables, leptin, and adiponectin were studied at baseline and 3 and 6 months after cabergoline treatment. Results: Patients with prolactinoma had increased level of fasting plasma glucose (P < 0.001) as compared to age-, gender-, and BMI-matched healthy controls. Estradiol concentration of controls was higher than that of patients (P = 0.018). Patients with prolactinoma had higher levels of leptin (P = 0.027) as compared to healthy controls without a significant difference in adiponectin levels. There was a significant decrease of body weight at 3 months (P = 0.029), with a further decline at 6 months (P < 0.001) of cabergoline therapy. Furthermore, there was a significant decrement of BMI (P < 0.001), waist circumference (P = 0.003), waist-hip ratio (P = 0.03), total body fat (P = 0.003), plasma glucose (P < 0.001), leptin levels (P = 0.013), and an increase in estradiol concentration (P = 0.03) at 6 months of cabergoline treatment. Conclusion: Patients with prolactinoma have adverse metabolic profile compared to matched controls. Normalization of PRL with cabergoline corrects all the metabolic abnormalities. PMID:27042412

  7. Hypothalamic Leptin Gene Therapy Reduces Bone Marrow Adiposity in ob/ob Mice Fed Regular and High-Fat Diets.

    PubMed

    Lindenmaier, Laurence B; Philbrick, Kenneth A; Branscum, Adam J; Kalra, Satya P; Turner, Russell T; Iwaniec, Urszula T

    2016-01-01

    Low bone mass is often associated with elevated bone marrow adiposity. Since osteoblasts and adipocytes are derived from the same mesenchymal stem cell (MSC) progenitor, adipocyte formation may increase at the expense of osteoblast formation. Leptin is an adipocyte-derived hormone known to regulate energy and bone metabolism. Leptin deficiency and high-fat diet-induced obesity are associated with increased marrow adipose tissue (MAT) and reduced bone formation. Short-duration studies suggest that leptin treatment reduces MAT and increases bone formation in leptin-deficient ob/ob mice fed a regular diet. Here, we determined the long-duration impact of increased hypothalamic leptin on marrow adipocytes and osteoblasts in ob/ob mice following recombinant adeno-associated virus (rAAV) gene therapy. Eight- to 10-week-old male ob/ob mice were randomized into four groups: (1) untreated, (2) rAAV-Lep, (3) rAAV-green fluorescent protein (rAAV-GFP), or (4) pair-fed to rAAV-Lep. For vector administration, mice were injected intracerebroventricularly with either rAAV-leptin gene therapy (rAAV-Lep) or rAAV-GFP (9 × 10(7) particles) and maintained for 30 weeks. In a second study, the impact of increased hypothalamic leptin levels on MAT was determined in mice fed high-fat diets; ob/ob mice were randomized into two groups and treated with either rAAV-Lep or rAAV-GFP. At 7 weeks post-vector administration, half the mice in each group were switched to a high-fat diet for 8 weeks. Wild-type (WT) controls included age-matched mice fed regular or high-fat diet. High-fat diet resulted in a threefold increase in MAT in WT mice, whereas MAT was increased by leptin deficiency up to 50-fold. Hypothalamic leptin gene therapy increased osteoblast perimeter and osteoclast perimeter with minor change in cancellous bone architecture. The gene therapy decreased MAT levels in ob/ob mice fed regular or high-fat diet to values similar to WT mice fed regular diet. These findings suggest

  8. Hypothalamic Leptin Gene Therapy Reduces Bone Marrow Adiposity in ob/ob Mice Fed Regular and High-Fat Diets.

    PubMed

    Lindenmaier, Laurence B; Philbrick, Kenneth A; Branscum, Adam J; Kalra, Satya P; Turner, Russell T; Iwaniec, Urszula T

    2016-01-01

    Low bone mass is often associated with elevated bone marrow adiposity. Since osteoblasts and adipocytes are derived from the same mesenchymal stem cell (MSC) progenitor, adipocyte formation may increase at the expense of osteoblast formation. Leptin is an adipocyte-derived hormone known to regulate energy and bone metabolism. Leptin deficiency and high-fat diet-induced obesity are associated with increased marrow adipose tissue (MAT) and reduced bone formation. Short-duration studies suggest that leptin treatment reduces MAT and increases bone formation in leptin-deficient ob/ob mice fed a regular diet. Here, we determined the long-duration impact of increased hypothalamic leptin on marrow adipocytes and osteoblasts in ob/ob mice following recombinant adeno-associated virus (rAAV) gene therapy. Eight- to 10-week-old male ob/ob mice were randomized into four groups: (1) untreated, (2) rAAV-Lep, (3) rAAV-green fluorescent protein (rAAV-GFP), or (4) pair-fed to rAAV-Lep. For vector administration, mice were injected intracerebroventricularly with either rAAV-leptin gene therapy (rAAV-Lep) or rAAV-GFP (9 × 10(7) particles) and maintained for 30 weeks. In a second study, the impact of increased hypothalamic leptin levels on MAT was determined in mice fed high-fat diets; ob/ob mice were randomized into two groups and treated with either rAAV-Lep or rAAV-GFP. At 7 weeks post-vector administration, half the mice in each group were switched to a high-fat diet for 8 weeks. Wild-type (WT) controls included age-matched mice fed regular or high-fat diet. High-fat diet resulted in a threefold increase in MAT in WT mice, whereas MAT was increased by leptin deficiency up to 50-fold. Hypothalamic leptin gene therapy increased osteoblast perimeter and osteoclast perimeter with minor change in cancellous bone architecture. The gene therapy decreased MAT levels in ob/ob mice fed regular or high-fat diet to values similar to WT mice fed regular diet. These findings suggest

  9. Hypothalamic Leptin Gene Therapy Reduces Bone Marrow Adiposity in ob/ob Mice Fed Regular and High-Fat Diets

    PubMed Central

    Lindenmaier, Laurence B.; Philbrick, Kenneth A.; Branscum, Adam J.; Kalra, Satya P.; Turner, Russell T.; Iwaniec, Urszula T.

    2016-01-01

    Low bone mass is often associated with elevated bone marrow adiposity. Since osteoblasts and adipocytes are derived from the same mesenchymal stem cell (MSC) progenitor, adipocyte formation may increase at the expense of osteoblast formation. Leptin is an adipocyte-derived hormone known to regulate energy and bone metabolism. Leptin deficiency and high-fat diet-induced obesity are associated with increased marrow adipose tissue (MAT) and reduced bone formation. Short-duration studies suggest that leptin treatment reduces MAT and increases bone formation in leptin-deficient ob/ob mice fed a regular diet. Here, we determined the long-duration impact of increased hypothalamic leptin on marrow adipocytes and osteoblasts in ob/ob mice following recombinant adeno-associated virus (rAAV) gene therapy. Eight- to 10-week-old male ob/ob mice were randomized into four groups: (1) untreated, (2) rAAV-Lep, (3) rAAV-green fluorescent protein (rAAV-GFP), or (4) pair-fed to rAAV-Lep. For vector administration, mice were injected intracerebroventricularly with either rAAV-leptin gene therapy (rAAV-Lep) or rAAV-GFP (9 × 107 particles) and maintained for 30 weeks. In a second study, the impact of increased hypothalamic leptin levels on MAT was determined in mice fed high-fat diets; ob/ob mice were randomized into two groups and treated with either rAAV-Lep or rAAV-GFP. At 7 weeks post-vector administration, half the mice in each group were switched to a high-fat diet for 8 weeks. Wild-type (WT) controls included age-matched mice fed regular or high-fat diet. High-fat diet resulted in a threefold increase in MAT in WT mice, whereas MAT was increased by leptin deficiency up to 50-fold. Hypothalamic leptin gene therapy increased osteoblast perimeter and osteoclast perimeter with minor change in cancellous bone architecture. The gene therapy decreased MAT levels in ob/ob mice fed regular or high-fat diet to values similar to WT mice fed regular diet. These findings suggest

  10. Keeping circadian time with hormones.

    PubMed

    Challet, E

    2015-09-01

    Daily variations of metabolism, physiology and behaviour are controlled by a network of coupled circadian clocks, comprising a master clock in the suprachiasmatic nuclei of the hypothalamus and a multitude of secondary clocks in the brain and peripheral organs. Light cues synchronize the master clock that conveys temporal cues to other body clocks via neuronal and hormonal signals. Feeding at unusual times can reset the phase of most peripheral clocks. While the neuroendocrine aspect of circadian regulation has been underappreciated, this review aims at showing that the role of hormonal rhythms as internal time-givers is the rule rather than the exception. Adrenal glucocorticoids, pineal melatonin and adipocyte-derived leptin participate in internal synchronization (coupling) within the multi-oscillatory network. Furthermore, pancreatic insulin is involved in food synchronization of peripheral clocks, while stomach ghrelin provides temporal signals modulating behavioural anticipation of mealtime. Circadian desynchronization induced by shift work or chronic jet lag has harmful effects on metabolic regulation, thus favouring diabetes and obesity. Circadian deregulation of hormonal rhythms may participate in internal desynchronization and associated increase in metabolic risks. Conversely, adequate timing of endocrine therapies can promote phase-adjustment of the master clock (e.g. via melatonin agonists) and peripheral clocks (e.g. via glucocorticoid agonists).

  11. Serum leptin, thyroxine and thyroid-stimulating hormone levels interact to affect cognitive function among US adults: evidence from a large representative survey.

    PubMed

    Beydoun, May A; Beydoun, Hind A; Shroff, Monal R; Kitner-Triolo, Melissa H; Zonderman, Alan B

    2012-08-01

    Neuroanatomical connections point to possible interactions between areas influencing energy homeostasis and those influencing cognition. We assessed whether serum leptin, thyroxine, and thyroid stimulating hormone (TSH) levels are associated with and interact to influence cognitive performance among US adults. Data from the National Health and Nutrition Examination Survey III (1988-1994) were used. Measures included a battery of neuropsychological tests and serum leptin, thyroxine, and TSH levels (20-59-year-old: n = 1114-2665; 60-90-year-old: n = 1365-5519). Among those 20-59-year-old, the middle tertile of leptin (vs. first tertile) was inversely related to the number of errors on the symbol digits substitution test. Increased thyroxine level was associated with a poorer performance on the serial digits test in the 20-59-year-old, but a better performance on the math test in 60-90-year-old group. TSH was associated with poor performance on various tests in the 20-59-year-old, but better performance in the 60-90-year-old group. Significant antagonistic interactions were found in both age groups between thyroxine, TSH, and leptin for a number of tests, including between leptin and thyroxine in the 60-90-year-old group in their association with word recall-correct score. We found significant associations of our main exposures with cognitive function among US adults, going in opposite directions between age groups in the cases of thyroid hormonal levels, as well as some interactive effects between exposures. It is important to conduct prospective cohort studies to provide further insight into potential interventions that would assess interactive effects of various hormonal replacement regimens.

  12. Influence of season and nutritional status on the direct effects of leptin, orexin-A and ghrelin on luteinizing hormone and growth hormone secretion in the ovine pituitary explant model.

    PubMed

    Kirsz, K; Szczesna, M; Dudek, K; Bartlewski, P M; Zieba, D A

    2014-07-01

    The aim of this study was to examine whether leptin (anorexigenic peptide), orexin-A, and ghrelin (orexigenic peptides) could directly (ie, independently of hypothalamic influences) affect the secretion of luteinizing hormone (LH) and growth hormone (GH) by adenohypophyseal (AP) explants obtained from normally fed or fasted (48 h) ewes during the breeding and nonbreeding seasons. In addition, a specific ovine super leptin antagonist (SLAN-3) was used to assess the interactions between leptin and ghrelin and/or orexin-A. Pituitary glands from 16 ovariectomized Polish Longwool ewes that had received estradiol-releasing subcutaneous implants were collected in the breeding (November; n = 8) and nonbreeding (May; n = 8) seasons. The AP explants were incubated for 240 min in a gas-liquid interface and treated with leptin (50 ng/mL), ghrelin (100 ng/mL), orexin-A (100 ng/mL), and SLAN-3 (500 ng/mL) with orexin-A or ghrelin. Treatments with leptin and SLAN-3 + orexin-A increased (P < 0.05) LH concentrations in the cultures of AP explants from fasted animals in the breeding season. Orexin-A increased (P < 0.05) LH secretion by AP explants from both fasted and fed animals in the breeding season. Ghrelin stimulated (P < 0.05) GH secretion by AP explants collected from fasted animals in nonbreeding season and from normally fed ewes in both seasons. Leptin decreased (P < 0.05) GH secretion by AP explants collected from fasted ewes in both seasons and from nonfasted ewes in the breeding season. However, the treatment with SLAN-3 + ghrelin resulted in greater (P < 0.05) GH concentrations compared with leptin treatment of AP explants from fasted ewes in the breeding season and from normally fed ewes in nonbreeding season. In summary, leptin, orexin-A, and ghrelin exerted direct effects on AP secretory function in an ex situ model and both the reproductive season and nutritional status of the animals impinged on the direct effects of the peptides on LH and GH release

  13. Leptin stimulates hepatic growth hormone receptor and insulin-like growth factor gene expression in a teleost fish, the hybrid striped bass.

    PubMed

    Won, Eugene T; Douros, Jonathan D; Hurt, David A; Borski, Russell J

    2016-04-01

    Leptin is an anorexigenic peptide hormone that circulates as an indicator of adiposity in mammals, and functions to maintain energy homeostasis by balancing feeding and energy expenditure. In fish, leptin tends to be predominantly expressed in the liver, another important energy storing tissue, rather than in fat depots as it is in mammals. The liver also produces the majority of circulating insulin-like growth factors (IGFs), which comprise the mitogenic component of the growth hormone (GH)-IGF endocrine growth axis. Based on similar regulatory patterns of leptin and IGFs that we have documented in previous studies on hybrid striped bass (HSB: Morone saxatilis×Morone chrysops), and considering the co-localization of these peptides in the liver, we hypothesized that leptin might regulate the endocrine growth axis in a manner that helps coordinate somatic growth with energy availability. Using a HSB hepatocyte culture system to simulate autocrine or paracrine exposure that might occur within the liver, this study examines the potential for leptin to modulate metabolism and growth through regulation of IGF gene expression directly, or indirectly through the regulation of GH receptors (GHR), which mediate GH-induced IGF expression. First, we verified that GH (50nM) has a classical stimulatory effect on IGF-1 and additionally show it stimulates IGF-2 transcription in hepatocytes. Leptin (5 and/or 50nM) directly stimulated in vitro GHR2 gene expression within 8h of exposure, and both GHR1 and GHR2 as well as IGF-1 and IGF-2 gene expression after 24h. Cells were then co-incubated with submaximal concentrations of leptin and GH (25nM each) to test if they had a synergistic effect on IGF gene expression, possibly through increased GH sensitivity following GHR upregulation by leptin. In combination, however, the treatments only had an additive effect on stimulating IGF-1 mRNA despite their capacity to increase GHR mRNA abundance. This suggests that leptin's stimulatory

  14. Leptin stimulates hepatic growth hormone receptor and insulin-like growth factor gene expression in a teleost fish, the hybrid striped bass.

    PubMed

    Won, Eugene T; Douros, Jonathan D; Hurt, David A; Borski, Russell J

    2016-04-01

    Leptin is an anorexigenic peptide hormone that circulates as an indicator of adiposity in mammals, and functions to maintain energy homeostasis by balancing feeding and energy expenditure. In fish, leptin tends to be predominantly expressed in the liver, another important energy storing tissue, rather than in fat depots as it is in mammals. The liver also produces the majority of circulating insulin-like growth factors (IGFs), which comprise the mitogenic component of the growth hormone (GH)-IGF endocrine growth axis. Based on similar regulatory patterns of leptin and IGFs that we have documented in previous studies on hybrid striped bass (HSB: Morone saxatilis×Morone chrysops), and considering the co-localization of these peptides in the liver, we hypothesized that leptin might regulate the endocrine growth axis in a manner that helps coordinate somatic growth with energy availability. Using a HSB hepatocyte culture system to simulate autocrine or paracrine exposure that might occur within the liver, this study examines the potential for leptin to modulate metabolism and growth through regulation of IGF gene expression directly, or indirectly through the regulation of GH receptors (GHR), which mediate GH-induced IGF expression. First, we verified that GH (50nM) has a classical stimulatory effect on IGF-1 and additionally show it stimulates IGF-2 transcription in hepatocytes. Leptin (5 and/or 50nM) directly stimulated in vitro GHR2 gene expression within 8h of exposure, and both GHR1 and GHR2 as well as IGF-1 and IGF-2 gene expression after 24h. Cells were then co-incubated with submaximal concentrations of leptin and GH (25nM each) to test if they had a synergistic effect on IGF gene expression, possibly through increased GH sensitivity following GHR upregulation by leptin. In combination, however, the treatments only had an additive effect on stimulating IGF-1 mRNA despite their capacity to increase GHR mRNA abundance. This suggests that leptin's stimulatory

  15. Leptin response to endogenous acute stress is independent of pituitary function.

    PubMed

    Schafroth, U; Godang, K; Ueland, T; Bollerslev, J

    2001-09-01

    There are close interactions between the adipocyte-derived hormone, leptin, and the anterior pituitary, especially the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the relationship between the sympathetic adrenergic system and serum leptin levels, dependent on the function of anterior pituitary hormone axes, in 27 patients without a history of a hormone-secreting pituitary adenoma or other underlying endocrine disease. Based on responses in a routine insulin hypoglycemia test (ITT), the patients were classified as hypopituitary (HP; n=15), growth hormone deficient (GHD; n=6) or controls (CTR; 6 patients with normal responses). Nadir plasma glucose was 1.5+/-0.1 mmol/l at the time of maximum hypoglycemia. Each group had a significant increase in plasma epinephrine; however the magnitude of change was significantly higher in GHD (6.066+/-1.633 nmol/l) compared with HP patients (1.781+/-0.492 nmol/l) (P<0.01). The rise in norepinephrine was delayed (60 min) in the HP and CTR groups. However, in GHD patients there was a considerable increase at the time of hypoglycemia which was significantly different from HP (P<0.001) and CTR (P<0.05) patients. The increase in catecholamines was followed by a quick and significant decrease in serum leptin levels 45 min after an i.v. bolus injection of insulin in HP patients (-4.7+/-2.5%, P<0.05), which was significantly sustained after 60 min (-5.6+/-2.5%, P<0.05). In CTR patients there was a significant decrease in serum leptin levels 60 min after i.v. insulin (-14.4+/-6.9%, P<0.05), while no significant response was observed in the GHD group, although 5 of 6 patients had decreased levels at 45 and 60 min. No differences between the groups were found by ANOVA. In conclusion, an acute increase in endogenous circulating catecholamines is associated with a quick decrease in serum leptin levels. Intact anterior pituitary function seems not to be essential for this hitherto poorly understood mechanism.

  16. Leptin and its receptor in hematologic malignancies

    PubMed Central

    Han, Tian-Jie; Wang, Xin

    2015-01-01

    Leptin is an adipocyte-derived cytokine coded by the obese gene, not only regulates metabolism, but also participates in hematopoiesis. Aberrant leptin levels in patients with hematologic malignancies were observed and associates with clinical characters, such as body mass index (BMI), gender, blast cell percentage. Leptin concentrations alter while diseases progress or remission. Leptin receptor is expressed in hematopoietic CD34+ stem cells, erythrocytes, lymphocytes, blast cells and samples in leukemia and lymphoma patients. The adipokine stimulates cell proliferation, cytokine secretion and protects malignant cells from apoptosis through Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and extracellular signal activated kinase 1/2 (MAPK/ERK1/2), or 3 kinase (PI3K) signaling pathways. These findings indicate leptin signaling possibility take part in occurrence, progression and prognosis of hematologic malignancies. This article reviews leptin/leptin receptor expression and the correlations with clinical characters, treatment and prognosis in myeloid and lymphoid neoplasms. PMID:26884894

  17. Endogenous sulfur dioxide is a novel adipocyte-derived inflammatory inhibitor

    PubMed Central

    Zhang, Heng; Huang, Yaqian; Bu, Dingfang; Chen, Selena; Tang, Chaoshu; Wang, Guang; Du, Junbao; Jin, Hongfang

    2016-01-01

    The present study was designed to determine whether sulfur dioxide (SO2) could be endogenously produced in adipocyte and served as a novel adipocyte-derived inflammatory inhibitor. SO2 was detected in adipose tissue using high-performance liquid chromatography with fluorescence detection. SO2 synthase aspartate aminotransferase (AAT1 and AAT2) mRNA and protein expressions in adipose tissues were measured. For in vitro study, 3T3-L1 adipocytes were cultured, infected with adenovirus carrying AAT1 gene or lentivirus carrying shRNA to AAT1, and then treated with tumor necrosis factor-α (TNF-α). We found that endogenous SO2/AAT pathway existed in adipose tissues including perivascular, perirenal, epididymal, subcutaneous and brown adipose tissue. AAT1 overexpression significantly increased SO2 production and inhibited TNF-α-induced inflammatory factors, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) secretion from 3T3-L1 adipocytes. By contrast, AAT1 knockdown decreased SO2 production and exacerbated TNF-α-stimulated MCP-1 and IL-8 secretion. Mechanistically, AAT1 overexpression attenuated TNF-α-induced IκBα phosphorylation and degradation, and nuclear factor-κB (NF-κB) p65 phosphorylation, while AAT1 knockdown aggravated TNF-α-activated NF-κB pathway, which was blocked by SO2. NF-κB inhibitors, PDTC or Bay 11-7082, abolished excessive p65 phosphorylation and adipocyte inflammation induced by AAT1 knockdown. This is the first report to suggest that endogenous SO2 is a novel adipocyte-derived inflammatory inhibitor. PMID:27246393

  18. Endogenous sulfur dioxide is a novel adipocyte-derived inflammatory inhibitor.

    PubMed

    Zhang, Heng; Huang, Yaqian; Bu, Dingfang; Chen, Selena; Tang, Chaoshu; Wang, Guang; Du, Junbao; Jin, Hongfang

    2016-01-01

    The present study was designed to determine whether sulfur dioxide (SO2) could be endogenously produced in adipocyte and served as a novel adipocyte-derived inflammatory inhibitor. SO2 was detected in adipose tissue using high-performance liquid chromatography with fluorescence detection. SO2 synthase aspartate aminotransferase (AAT1 and AAT2) mRNA and protein expressions in adipose tissues were measured. For in vitro study, 3T3-L1 adipocytes were cultured, infected with adenovirus carrying AAT1 gene or lentivirus carrying shRNA to AAT1, and then treated with tumor necrosis factor-α (TNF-α). We found that endogenous SO2/AAT pathway existed in adipose tissues including perivascular, perirenal, epididymal, subcutaneous and brown adipose tissue. AAT1 overexpression significantly increased SO2 production and inhibited TNF-α-induced inflammatory factors, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) secretion from 3T3-L1 adipocytes. By contrast, AAT1 knockdown decreased SO2 production and exacerbated TNF-α-stimulated MCP-1 and IL-8 secretion. Mechanistically, AAT1 overexpression attenuated TNF-α-induced IκBα phosphorylation and degradation, and nuclear factor-κB (NF-κB) p65 phosphorylation, while AAT1 knockdown aggravated TNF-α-activated NF-κB pathway, which was blocked by SO2. NF-κB inhibitors, PDTC or Bay 11-7082, abolished excessive p65 phosphorylation and adipocyte inflammation induced by AAT1 knockdown. This is the first report to suggest that endogenous SO2 is a novel adipocyte-derived inflammatory inhibitor. PMID:27246393

  19. Inflammatory markers and adipokines alter adipocyte-derived ASP production through direct and indirect immune interaction.

    PubMed

    Lu, H; Gauvreau, D; Tom, F-Q; Lapointe, M; Luo, X P; Cianflone, K

    2013-04-01

    Obesity and related metabolic diseases are associated with chronic low-grade inflammation, characterized by increased pro-inflammatory proteins. Several studies have demonstrated increases in acylation stimulating protein (ASP) and its precursor protein C3 in obesity, diabetes and dyslipidemia. To evaluate the effects of acute inflammatory factors and adipokines on ASP production and potential mechanisms of action, 3T3-L1 adipocytes were treated for 24 h with adipokines, cytokines, macrophage-conditioned media and direct co-culture with J774 macrophages. ASP and C3 in the media were evaluated in relation to changes in adipocyte lipid metabolism (cellular triglyceride stores). Leptin, adiponectin, IL-10, LPS and TNF-α increased ASP production (151%, 153%, 190%, 318%, 134%, P<0.05, respectively,). C5a and RANTES (Regulated and normal T cell expressed and secreted) decreased ASP production ( - 34%, - 47%, P<0.05), which was also associated with a decrease in the precursor protein C3 ( - 39% to - 51%, P<0.01), while keratinocyte chemoattractant (KC; murine IL-8 ortholog) had no effect on ASP and C3 secretion. By contrast, apelin, omentin and visfatin also decreased ASP ( - 27%, - 49%, - 22%, P<0.05), but without changes in precursor protein C3 secretion. Macrophage-conditioned media alone had little effect on C3 or ASP, while co-culture of adipocytes with macrophages markedly increased ASP and C3 production (272%, 167%, P<0.05). These in vitro results suggest various metabolic hormones and inflammatory factors can affect ASP production through increased precursor C3 production and/or by changing the rate of C3 conversion to ASP. As an adipokine, ASP could constitute a new link between adipocytes and macrophages.

  20. Impact of single nucleotide polymorphisms in leptin, leptin receptor, growth hormone receptor, and diacylglycerol acyltransferase (DGAT1) gene loci on milk production, feed, and body energy traits of UK dairy cows.

    PubMed

    Banos, G; Woolliams, J A; Woodward, B W; Forbes, A B; Coffey, M P

    2008-08-01

    The impact of 9 single nucleotide polymorphisms (SNP) in the leptin (LEP), leptin receptor (LEPR), growth hormone receptor (GHR), and diacylglycerol acyltransferase (DGAT1) gene loci on daily milk production, feed intake, and feed conversion, and weekly measures of live weight, BCS, and body energy traits was evaluated using genetic and phenotypic data on 571 Holstein cows raised at the Langhill Dairy Cattle Research Center in Scotland. Six SNP were typed on the LEP gene and 1 on each of the other 3 loci. Of the 6 LEP SNP, 3 were in very high linkage disequilibrium, meaning there is little gain in typing all of them in the future. Seven LEP haplotypes were identified by parsimony-based analyses. Random-regression allele-substitution models were used to assess the impact of each SNP allele or haplotype on the traits of interest. Diacylglycerol acyltransferase had a significant effect on milk yield, whereas GHR significantly affected feed intake, feed conversion, and body energy traits. There was also evidence of dominance in allelic effects on milk yield and BCS. The LEP haplotype CCGTTT (corresponding to leptin SNP C207T, C528T, A1457G, C963T, A252T, and C305T, respectively) significantly affected milk yield and feed and dry matter intake. Animals carrying this haplotype produced 3.13 kg more milk daily and consumed 4.64 kg more feed. Furthermore, they tended to preserve more energy than average. Such results may be used to facilitate genetic selection in animal breeding programs.

  1. Low energy availability in exercising men is associated with reduced leptin and insulin but not with changes in other metabolic hormones.

    PubMed

    Koehler, Karsten; Hoerner, Neele R; Gibbs, Jenna C; Zinner, Christoph; Braun, Hans; De Souza, Mary Jane; Schaenzer, Wilhelm

    2016-10-01

    Low energy availability, defined as low caloric intake relative to exercise energy expenditure, has been linked to endocrine alterations frequently observed in chronically energy-deficient exercising women. Our goal was to determine the endocrine effects of low energy availability in exercising men. Six exercising men (VO2peak: 49.3 ± 2.4 ml · kg(-1) · min(-1)) underwent two conditions of low energy availability (15 kcal · kg(-1) fat-free mass [FFM] · day(-1)) and two energy-balanced conditions (40 kcal · kg(-1) FFM · day(-1)) in randomised order. During one low energy availability and one balanced condition, participants exercised to expend 15 kcal · kg(-1) FFM · day(-1); no exercise was conducted during the other two conditions. Metabolic hormones were assessed before and after each 4-day period. Following both low energy availability conditions, leptin (-53% to -56%) and insulin (-34% to -38%) were reduced (P < 0.05). Reductions in leptin and insulin were independent of whether low energy availability was attained with or without exercise (P > 0.80). Low energy availability did not significantly impact ghrelin, triiodothyronine, testosterone and IGF-1 (all P > 0.05). The observed reductions in leptin and insulin were in the same magnitude as changes previously reported in sedentary women. Further research is needed to understand why other metabolic hormones are more robust against low energy availability in exercising men than those in sedentary and exercising women.

  2. Leptin: a potential novel antidepressant.

    PubMed

    Lu, Xin-Yun; Kim, Chung Sub; Frazer, Alan; Zhang, Wei

    2006-01-31

    Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders. PMID:16423896

  3. The role of leptin in obesity and the potential for leptin replacement therapy.

    PubMed

    Feng, Helin; Zheng, Lihua; Feng, Zhangying; Zhao, Yaheng; Zhang, Ning

    2013-08-01

    Leptin (from the Greek word "lepto'' meaning "thin") is a 167-amino acid peptide hormone encoded by the obesity (ob) gene and secreted by white adipocytes. Blood leptin concentrations are increased in obese individuals. Leptin is a satiety hormone that provides negative feedback to the hypothalamus, controlling appetite and energy expenditure. Leptin binds to presynaptic GABAergic neurons to produce its effect, raising the distinct possibility that GABAergic axon terminals are the ultimate subcellular site of action for its effects. Released into the circulation, leptin crosses the blood-brain barrier and binds to leptin receptors, influencing the activity of various hypothalamic neurons, as well as encoding orexigenic and anorexigenic neuropeptides. Moreover, leptin affects a wide range of metabolic functions in the peripheral tissue. In this review, we discuss some physiologic functions of leptin, including effects on obesity and some effects of leptin replacement therapy. PMID:23274948

  4. Leptin promotes cell proliferation and survival of trophoblastic cells.

    PubMed

    Magariños, María Paula; Sánchez-Margalet, Víctor; Kotler, Mónica; Calvo, Juan Carlos; Varone, Cecilia L

    2007-02-01

    Leptin, the 16-kDa protein product of the obese gene, was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in placenta. In the present work, we studied a possible effect of leptin on trophoblastic cell proliferation, survival, and apoptosis. Recombinant human leptin added to JEG-3 and BeWo choriocarcinoma cell lines showed a stimulatory effect on cell proliferation up to 3 and 2.4 times, respectively, measured by (3)H-thymidine incorporation and cell counting. These effects were time and dose dependent. Maximal effect was achieved at 250 ng leptin/ml for JEG-3 cells and 50 ng leptin/ml for BeWo cells. Moreover, by inhibiting endogenous leptin expression with 2 microM of an antisense oligonucleotide (AS), cell proliferation was diminished. We analyzed cell population distribution during the different stages of cell cycle by fluorescence-activated cell sorting, and we found that leptin treatment displaced the cells towards a G2/M phase. We also found that leptin upregulated cyclin D1 expression, one of the key cell cycle-signaling proteins. Since proliferation and death processes are intimately related, the effect of leptin on cell apoptosis was investigated. Treatment with 2 microM leptin AS increased the number of apoptotic cells 60 times, as assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, and the caspase-3 activity was increased more than 2 fold. This effect was prevented by the addition of 100 ng leptin/ml. In conclusion, we provide evidence that suggests that leptin is a trophic and mitogenic factor for trophoblastic cells by virtue of its inhibiting apoptosis and promoting proliferation. PMID:17021346

  5. Consequence of Menin Deficiency in Mouse Adipocytes Derived by In Vitro Differentiation

    PubMed Central

    Parekh, Vaishali I.; Modali, Sita D.; Desai, Shruti S.; Agarwal, Sunita K.

    2015-01-01

    Lipoma in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome is a type of benign fat-cell tumor that has biallelic inactivation of MEN1 that encodes menin and could serve as a model to investigate normal and pathologic fat-cell (adipocyte) proliferation and function. The role of menin and its target genes in adipocytes is not known. We used in vitro differentiation to derive matched normal and menin-deficient adipocytes from wild type (WT) and menin-null (Men1-KO) mouse embryonic stem cells (mESCs), respectively, or 3T3-L1 cells without or with menin knockdown to investigate cell size, lipid content, and gene expression changes. Adipocytes derived from Men1-KO mESCs or after menin knockdown in 3T3-L1 cells showed a 1.5–1.7-fold increase in fat-cell size. Global gene expression analysis of mESC-derived adipocytes showed that lack of menin downregulated the expression of many differentially methylated genes including the tumor suppressor long noncoding RNA Meg3 but upregulated gene expression from the prolactin gene family locus. Our results show that menin deficiency leads to fat-cell hypertrophy and provide model systems that could be used to study the regulation of fat-cell size. PMID:26229531

  6. Role of leptin in reproduction.

    PubMed

    Mantzoros, C S

    2000-01-01

    Leptin is a 16-kDa adipocyte-secreted protein the serum levels of which reflect mainly the amount of energy stores but are also influenced by short-term energy imbalance as well as several cytokines and hormones. Leptin, by binding to specific receptors, alters the expression of several hypothalamic neuropeptides that regulate neuroendocrine function as well as energy intake and expenditure. More specifically, accumulating evidence suggests that this hormone may serve to signal to the brain information on the critical amount of fat stores that are necessary for LHRH secretion and activation of the hypothalamic-pituitary-gonadal axis. Rising leptin levels have been associated with initiation of puberty in animals and humans and normal leptin levels are needed for maintenance of menstrual cycles and normal reproductive function. Moreover, circadian and ultradian variations of leptin levels are associated with minute to minute variations of LH and estradiol in normal women. Falling leptin levels in response to starvation result in decreased estradiol levels and amenorrhea in subjects with anorexia nervosa or strenuously exercising athletes. In addition, leptin has a potentially important role during pregnancy and in the physiology of the neonate. Finally, recent evidence suggests that leptin may influence ovarian steroidogenesis directly, but the exact role of intraovarian leptin action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated.

  7. Leptin Regulation of Immune Responses.

    PubMed

    Naylor, Caitlin; Petri, William A

    2016-02-01

    Leptin is a regulatory hormone with multiple roles in the immune system. We favor the concept that leptin signaling 'licenses' various immune cells to engage in immune responses and/or to differentiate. Leptin is an inflammatory molecule that is capable of activating both adaptive and innate immunity. It can also 'enhance' immune functions, including inflammatory cytokine production in macrophages, granulocyte chemotaxis, and increased Th17 proliferation. Leptin can also 'inhibit' cells; CD4(+) T cells are inhibited from differentiating into regulatory T cells in the presence of elevated leptin, while NK cells can exhibit impaired cytotoxicity under the same circumstances. Consequently, understanding the effect of leptin signaling is important to appreciate various aspects of immune dysregulation observed in malnutrition, obesity, and autoimmunity.

  8. Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control

    PubMed Central

    Yan, Ai-Fen; Chen, Ting; Chen, Shuang; Ren, Chun-Hua; Hu, Chao-Qun; Cai, Yi-Ming; Liu, Fang; Tang, Dong-Sheng

    2016-01-01

    In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model. PMID:27249000

  9. Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control.

    PubMed

    Yan, Ai-Fen; Chen, Ting; Chen, Shuang; Ren, Chun-Hua; Hu, Chao-Qun; Cai, Yi-Ming; Liu, Fang; Tang, Dong-Sheng

    2016-01-01

    In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model. PMID:27249000

  10. Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control.

    PubMed

    Yan, Ai-Fen; Chen, Ting; Chen, Shuang; Ren, Chun-Hua; Hu, Chao-Qun; Cai, Yi-Ming; Liu, Fang; Tang, Dong-Sheng

    2016-01-01

    In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model.

  11. Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

    PubMed

    Bonda, David J; Stone, Jeremy G; Torres, Sandy L; Siedlak, Sandra L; Perry, George; Kryscio, Richard; Jicha, Gregory; Casadesus, Gemma; Smith, Mark A; Zhu, Xiongwei; Lee, Hyoung-Gon

    2014-01-01

    Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.

  12. Leptin in reproduction.

    PubMed

    Caprio, M; Fabbrini, E; Isidori, A M; Aversa, A; Fabbri, A

    2001-03-01

    In mammals, the function of the reproductive system is dependent on the availability of energy in the environment. It is well established that acute modifications of energy balance modulate the hypothalamic-pituitary-gonadal axis. In several species, fasting and caloric restriction have been shown to cause the suppression of pulsatile luteinizing hormone secretion, via an inhibition of the gonadotropin-releasing hormone pulse generator. Such a mechanism probably prevents energy being wasted for reproduction. By contrast, excessive energy storage and obesity interfere with the correct regulation of the reproductive axis. The identification of leptin and leptin receptors, along with studies performed in animal models of leptin deficiency and resistance, has focused attention on the role of this molecule in reproduction, and disclosed new aspects of the relationship between energy stores, adipose tissue and reproductive function. Here, we discuss the central and peripheral effects of leptin on reproductive tissues, and try to fit a complex reality into a simplified model. In particular, the roles of leptin in reproduction at different anatomical levels and in various clinical and experimental settings are discussed.

  13. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    PubMed Central

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  14. Development and characterization of high affinity leptins and leptin antagonists.

    PubMed

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  15. Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling.

    PubMed

    Wang, Z; Zhou, Y T; Kakuma, T; Lee, Y; Kalra, S P; Kalra, P S; Pan, W; Unger, R H

    2000-10-14

    Liver-derived hyperleptinemia induced in normal rats by adenovirus-induced gene transfer causes rapid disappearance of body fat, whereas the endogenous adipocyte-derived hyperleptinemia of obesity does not. Here we induce liver-derived hyperleptinemia in rats with adipocyte-derived hyperleptinemia of acquired obesity caused by ventromedial hypothalamus lesioning (VMH rats) or by feeding 60% fat (DIO rats). Liver-derived hyperleptinemia in obese rats caused only a 5-7% loss of body weight, compared to a 13% loss in normoleptinemic lean animals; but in actual grams of weight lost there was no significant difference between obese and lean groups, suggesting that a subset of cells remain leptin-sensitive in obesity. mRNA and protein of a putative leptin-resistance factor, suppressor of cytokine signaling (SOCS)-1 or -3, were both increased in white adipose tissues (WAT) of VMH and DIO rats. Since transgenic overexpression of SOCS-3 in islets reduced the lipopenic effect of leptin by 75%, we conclude that the increased expression of SOCS-1 and -3 in WAT of rats with acquired obesity could have blocked leptin's lipopenic action in the leptin-resistant WAT population.

  16. Leptin in teleostean fish, towards the origins of leptin physiology.

    PubMed

    Gorissen, Marnix; Flik, Gert

    2014-11-01

    Teleostean leptin was first cloned in 2005, more than a decade after the discovery of mammalian leptin. The reason for this delay lies in the very poor primary sequence conservation (∼13-25%) between mammalian and fish leptins. These low sequence conservations indicate a high degree of molecular evolvability and warrant a search for different and original functions of leptin in teleosts. Indeed, new and original insights are obtained because of the unique phylogenetic position of teleostean fish as the earliest vertebrates and because of their ectothermy, which means that teleosts are more flexible in changing their metabolism than mammals and leptin could play a role in this flexibility. Research during the last decade reveals that leptin is a truly pleiotropic hormone in fish and mammals alike, with functions among others in the regulation of food intake and body weight, development, but also in the regulation of the stress axis and acclimation processes to for instance low oxygen levels in the water. In this review, we provide an overview of the teleostean leptin work done in the last ten years, and demonstrate that the power of a comparative approach leads to new insights on the origins of leptin physiology. PMID:24977940

  17. Leptin regulates gallbladder genes related to absorption and secretion.

    PubMed

    Swartz-Basile, Deborah A; Lu, Debao; Basile, David P; Graewin, Shannon J; Al-Azzawi, Hayder; Kiely, James M; Mathur, Abhishek; Yancey, Kyle; Pitt, Henry A

    2007-07-01

    Dysregulation of gallbladder ion and water absorption and/or secretion has been linked to cholesterol crystal and gallstone formation. We have recently demonstrated that obese, leptin-deficient (Lep(ob)) mice have enlarged gallbladder volumes and decreased gallbladder contractility and that leptin administration to these mice normalizes gallbladder function. However, the effect of leptin on gallbladder absorption/secretion is not known. Therefore, we sought to determine whether leptin would alter the expression of genes involved in water and ion transport across the gallbladder epithelium. Affymetrix oligonucleotide microarrays representing 39,000 transcripts were used to compare gallbladder gene-expression profiles from 12-wk-old control saline-treated Lep(ob) and from leptin-treated Lep(ob) female mice. Leptin administration to Lep(ob) mice decreased gallbladder volume, bile sodium concentration, and pH. Leptin repletion upregulated the expression of aquaporin 1 water channel by 1.3-fold and downregulated aquaporin 4 by 2.3-fold. A number of genes involved in sodium transport were also influenced by leptin replacement. Epithelial sodium channel-alpha and sodium hydrogen exchangers 1 and 3 were moderately downregulated by 2.0-, 1.6-, and 1.3-fold, respectively. Carbonic anhydrase-IV, which plays a role in the acidification of bile, was upregulated 3.7-fold. In addition, a number of inflammatory cytokines that are known to influence gallbladder epithelial cell absorption and secretion were upregulated. Thus leptin, an adipocyte-derived cytokine involved with satiety and energy balance, influences gallbladder bile volume, sodium, and pH as well as multiple inflammatory cytokine genes and genes related to water, sodium, chloride, and bicarbonate transport.

  18. Leptin resistance in obesity: An epigenetic landscape.

    PubMed

    Crujeiras, Ana B; Carreira, Marcos C; Cabia, Begoña; Andrade, Sara; Amil, Maria; Casanueva, Felipe F

    2015-11-01

    Leptin is an adipocyte-secreted hormone that inhibits food intake and stimulates energy expenditure through interactions with neuronal pathways in the brain, particularly pathways involving the hypothalamus. Intact functioning of the leptin route is required for body weight and energy homeostasis. Given its function, the discovery of leptin increased expectations for the treatment of obesity. However, most obese individuals and subjects with a predisposition to regain weight after losing it have leptin concentrations than lean individuals, but despite the anorexigenic function of this hormone, appetite is not effectively suppressed in these individuals. This phenomenon has been deemed leptin resistance and could be the result of impairments at a number of levels in the leptin signalling pathway, including reduced access of the hormone to its receptor due to changes in receptor expression or changes in post-receptor signal transduction. Epigenetic regulation of the leptin signalling circuit could be a potential mechanism of leptin function disturbance. This review discusses the molecular mechanisms, particularly the epigenetic regulation mechanisms, involved in leptin resistance associated with obesity and the therapeutic potential of these molecular mechanisms in the battle against the obesity pandemic.

  19. Leptin as a modulator of neuroendocrine function in humans.

    PubMed

    Khan, Sami M; Hamnvik, Ole-Petter R; Brinkoetter, Mary; Mantzoros, Christos S

    2012-07-01

    Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.

  20. Structure, production and signaling of leptin

    PubMed Central

    Münzberg, Heike; Morrison, Christopher D.

    2014-01-01

    The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause morbid obesity, and it is now appreciated that obesity is caused by a dysregulation of central neuronal circuits. From the first discovery of the leptin deficient obese mouse (ob/ob), to the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, much has been learned about leptin and its action in the central nervous system. The initial high hopes that leptin would cure obesity were quickly dampened by the discovery that most obese humans have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint for distinct neuronal circuits that control energy homeostasis. A better understanding of the regulation and interconnection of these circuits will further guide and improve the development of safe and effective interventions to treat obesity. This review will highlight our current knowledge about the hormone leptin, its signaling pathways and its central actions to mediate distinct physiological functions. PMID:25305050

  1. Selection of non-competitive leptin antagonists using a random nanobody-based approach.

    PubMed

    Zabeau, Lennart; Verhee, Annick; Catteeuw, Dominiek; Faes, Liesbeth; Seeuws, Sylvie; Decruy, Tine; Elewaut, Dirk; Peelman, Frank; Tavernier, Jan

    2012-01-01

    The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models. PMID:21851341

  2. Leptin in Alzheimer's disease.

    PubMed

    Magalhães, C A; Carvalho, M G; Sousa, L P; Caramelli, P; Gomes, K B

    2015-10-23

    Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is histologically characterized by accumulation of amyloid-β protein (Aβ) on extracellular plaques and deposition of hyperphosphorylated tau protein in intracellular neurofibrillary tangles. Several studies have shown that obesity may precede dementia and that lifestyle factors play a critical role in the onset of AD. Furthermore, accumulating evidence indicates that obesity is an independent risk factor for developing AD. In this scenario, the understanding of the role of adipose tissue in brain health is essential to clarify the establishment of demential processes. The objective of this work was to review studies regarding leptin, an anorexigenic peptide hormone synthesized in adipocytes, in the context of dementia. Some authors proposed that leptin evaluation might be a better predictor of dementia than traditional anthropometric measures. Leptin, once established as a biomarker, could enhance the understanding of late-onset AD risk over the life course, as well as the clinical progression of prodromal state to manifested AD. Other studies have proposed that leptin presents neuroprotective activities, which could be explained by inhibiting the amyloidogenic process, reducing the levels of tau protein phosphorylation and improving the cognitive function.

  3. The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin.

    PubMed

    Folch, Jaume; Patraca, Iván; Martínez, Nohora; Pedrós, Ignacio; Petrov, Dmitry; Ettcheto, Miren; Abad, Sonia; Marin, Miguel; Beas-Zarate, Carlos; Camins, Antoni

    2015-11-01

    Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD). In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus. However, additional functions of Lep in the hippocampus and cortex have been unravelled in recent years. Early events in the sporadic form of AD likely involve cellular level alterations which can have an effect on food intake and metabolism. Thus, AD can be conceivably interpreted as a multiorgan pathology that not only results in a dramatic neuronal loss in brain areas such as the hippocampus and the cortex (ultimately leading to a significant cognitive impairment) but as a disease which also affects body-weight homeostasis. According to this view, body-weight control disruptions are to be expected in both the early- and late-stage AD, concomitant with changes in serum Lep content, alterations in Lep transport across the blood-brain barrier (BBB) and Lep receptor-related signalling abnormalities. Lep is a member of the adipokine family of molecules, while the Lep receptor belongs to the class I cytokine receptors. Since cellular response to adipokine signalling can be either potentiated or diminished as a result of specific ligand-receptor interactions, Lep interactions with other members of the adipokine family including amylin, ghrelin and hormones such as prolactin require further investigation. In this review, we provide a general perspective on the functions of Lep in the brain, with a particular focus on the sporadic AD.

  4. Circulating leptin and pain perception among tobacco-dependent individuals.

    PubMed

    al'Absi, Mustafa; Lemieux, Andrine; Nakajima, Motohiro; Hatsukami, Dorothy K; Allen, Sharon

    2015-04-01

    Recent preclinical evidence suggests that leptin may modulate the stress response and may increase nociception. In this study, we examined for the first time the extent to which cigarette smoking is associated with leptin levels during an extended rest period and in response to noxious stimuli. Repeated blood samples were collected during a laboratory session from smokers and nonsmokers and assayed for leptin. Pain experiences, as well as neuroendocrine and cardiovascular measures, were collected across cold pressor and thermal heat pain tests. Both analysis of variance and correlations confirmed that smokers demonstrated dysregulations in leptin responsivity and association with pain relative to nonsmokers. The flat pattern of leptin release and the weak associations of this hormone with pain in smokers suggest a long-term effect of tobacco dependence on this regulatory hormone. In light of leptin's influence on reward pathways, further investigation of leptin's involvement in nicotine dependence is warranted. PMID:25720946

  5. Leptin regulates gonadotropins and steroid receptors in the rats ovary.

    PubMed

    Silveira Cavalcante, Fernanda; Aiceles, Verónica; da Fonte Ramos, Cristiane

    2013-01-01

    The leptin hormone is important to satiety and an important link between the nutritional status and reproductive processes. Owing to the contradictory effects of leptin on the ovary and the failure to clarify the precise mechanism by which leptin affects the ovary, our aim was to contribute to evaluation if leptin can directly regulate the gene expression of leptin itself and its receptors, and the expression of several genes related to the ovary function by a model of tissue culture. Ovaries from Wistar dams were used at 90 days of age and were submitted to medium with presence and absence of leptin. The results can demonstrate that leptin regulates gonadotropins and steroid receptors, which could suggest that the ovarian leptin role could be secondary to the changes in these receptors expression in rats.

  6. Adipose tissue hyperplasia with enhanced adipocyte-derived stem cell activity in Tc1(C8orf4)-deleted mice

    PubMed Central

    Jang, Hayoung; Kim, Minsung; Lee, Soyoung; Kim, Jungtae; Woo, Dong-Cheol; Kim, Kyung Won; Song, Kyuyoung; Lee, Inchul

    2016-01-01

    Adipose tissue hyperplasia with increased number of adipocytes is implicated in a protective rather than deleterious effect on obesity-associated metabolic disorder. It is poorly understood how the adipose tissue cellularity is regulated. Tc1 is a gene of vertebrates that regulates diverse downstream genes. Young Tc1-deleted mice fed on standard chow diet show expanded adipose tissue with smaller adipocytes in size compared to wild type controls, representing adipose tissue hyperplasia. Tc1−/− mice show enhanced glucose tolerance and reduced serum lipids. Adipocyte-derived stem cells (ADSCs) from Tc1−/− mice show enhanced proliferative and adipogenic capacity compared to wild type controls, suggesting that the adipose hyperplasia is regulated at the stem cell level. PPARγ and CEBPα are up-regulated robustly in Tc1−/− ADSCs upon induction for adipogenesis. Wisp2 and Dlk1, inhibitors of adipogenesis, are down-regulated in Tc1−/− ADSCs compared to controls. Tc1-transfected NIH3T3 cells show higher β-catenin reporter signals than vector transfected controls, suggesting a role of canonical Wnt signaling in the Tc1-dependent adipose regulation. Our data support that Tc1 is a novel regulator for adipose stem cells. Adipose tissue hyperplasia may be implicated in the metabolic regulation of Tc1−/− mice. PMID:27775060

  7. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study...

  8. Leptin signalling pathways in hypothalamic neurons.

    PubMed

    Kwon, Obin; Kim, Ki Woo; Kim, Min-Seon

    2016-04-01

    Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways. PMID:26786898

  9. Leptin signalling pathways in hypothalamic neurons.

    PubMed

    Kwon, Obin; Kim, Ki Woo; Kim, Min-Seon

    2016-04-01

    Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways.

  10. Adipocyte iron regulates leptin and food intake

    PubMed Central

    Gao, Yan; Li, Zhonggang; Gabrielsen, J. Scott; Simcox, Judith A.; Lee, Soh-hyun; Jones, Deborah; Cooksey, Bob; Stoddard, Gregory; Cefalu, William T.; McClain, Donald A.

    2015-01-01

    Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression. PMID:26301810

  11. Dexamethasone and Acetate Modulate Cytoplasmic Leptin in Bovine Preadipocytes

    PubMed Central

    Yonekura, Shinichi; Hirota, Shohei; Tokutake, Yukako; Rose, Michael T.; Katoh, Kazuo; Aso, Hisashi

    2014-01-01

    Hormonal and nutrient signals regulate leptin synthesis and secretion. In rodents, leptin is stored in cytosolic pools of adipocytes. However, not much information is available regarding the regulation of intracellular leptin in ruminants. Recently, we demonstrated that leptin mRNA was expressed in bovine intramuscular preadipocyte cells (BIP cells) and that a cytoplasmic leptin pool may be present in preadipocytes. In the present study, we investigated the expression of cytoplasmic leptin protein in BIP cells during differentiation as well as the effects of various factors added to the differentiation medium on its expression in BIP cells. Leptin mRNA expression was observed only at 6 and 8 days after adipogenic induction, whereas the cytoplasmic leptin concentration was the highest on day 0 and decreased gradually thereafter. Cytoplasmic leptin was detected at 6 and 8 days after adipogenic induction, but not at 4 days after adipogenic induction. The cytoplasmic leptin concentration was reduced in BIP cells at 4 days after treatment with dexamethasone, whereas cytoplasmic leptin was not observed at 8 days after treatment. In contrast, acetate significantly enhanced the cytoplasmic leptin concentration in BIP cells at 8 days after treatment, although acetate alone did not induce adipocyte differentiation in BIP cells. These results suggest that dexamethasone and acetate modulate the cytoplasmic leptin concentration in bovine preadipocytes. PMID:25049989

  12. 20 years of leptin: role of leptin in human reproductive disorders.

    PubMed

    Chou, Sharon H; Mantzoros, Christos

    2014-10-01

    Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

  13. The response of the hypothalamic-pituitary-gonadal axis to fasting is modulated by leptin.

    PubMed

    Steiner, J; LaPaglia, N; Kirsteins, L; Emanuele, M; Emanuele, N

    2003-05-01

    Reproductive function is intimately related to caloric consumption. During fasting states, the hormones regulating reproduction, those of the hypothalamic-pituitary-gonadal axis, in particular, are severely altered. With the exciting observations that the obese (ob) gene product leptin, may also modulate neuroendocrine functions, we examined leptin's ability to prevent the consequences of fasting on reproductive hormones. Two groups of male rats, aged 65 days old, were either fasted and saline-injected or fasted and leptin-treated for approximately three days. Another group was given free access to rat chow. Leptin was able to prevent the fasting-induced fall of serum testosterone. Similar to testosterones dependence on leptin, leptin concentrations were somewhat dependent on testosterone. Castration accelerated the normal, age-related increase in serum leptin. Leptin also prevented the fasting-induced fall in luteinizing hormone (LH). The increase of beta-LH mRNA seen in the fasting state was prevented by leptin. There were no differences noted in luteinizing hormone releasing hormone (LHRH) mRNA among any of the groups. While neither fasting nor fasting plus leptin caused changes in serum prolactin, the increase in prolactin mRNA seen in fasted animals was prevented by leptin treatment. These data support the hypothesis that leptin plays a specific role in mediating the response of reproductive hormones to the nutritional status of the organism.

  14. Leptin and its receptors.

    PubMed

    Wada, Nobuhiro; Hirako, Satoshi; Takenoya, Fumiko; Kageyama, Haruaki; Okabe, Mai; Shioda, Seiji

    2014-11-01

    Leptin is mainly produced in the white adipose tissue before being secreted into the blood and transported across the blood-brain barrier. Leptin binds to a specific receptor (LepR) that has numerous subtypes (LepRa, LepRb, LepRc, LepRd, LepRe, and LepRf). LepRb, in particular, is expressed in several brain nuclei, including the arcuate nucleus, the paraventricular nucleus, and the dorsomedial, lateral and ventromedial regions of the hypothalamus. LepRb is also co-expressed with several neuropeptides, including proopiomelanocortin, neuropeptide Y, galanin, galanin-like peptide, gonadotropin-releasing hormone, tyrosine hydroxylase and neuropeptide W. Functionally, LepRb induces activation of the JAK2/ERK, /STAT3, /STAT5 and IRS/PI3 kinase signaling cascades, which are important for the regulation of energy homeostasis and appetite in mammals. In this review, we discuss the structure, genetics and distribution of the leptin receptors, and their role in cell signaling mechanisms. PMID:25218975

  15. Leptin and its receptors are present in the rat olfactory mucosa and modulated by the nutritional status.

    PubMed

    Baly, Christine; Aioun, Josiane; Badonnel, Karine; Lacroix, Marie-Christine; Durieux, Didier; Schlegel, Claire; Salesse, Roland; Caillol, Monique

    2007-01-19

    Leptin is an adipocyte-derived cytokine that regulates body weight mainly via the long form of the leptin receptor (Ob-Rb). Leptin and its receptors are expressed in several tissues, suggesting that leptin might also be effective peripherally. We hypothesized that, as shown in taste cells, leptin and its receptors isoforms (Ob-Rs) could be present in the rat olfactory mucosa (OM). Using RT-PCR, light and electron microscopy immunohistochemistry (ICC), we found that different isoforms of the receptor were expressed in OM and localized in sustentacular cells and in a subpopulation of maturating neurons; in addition, immunoreactivity was also present in differentiated neurons and enriched at the cilia membranes, where the odorants bind to their receptors. Moreover, using RT-PCR, ICC and RIA measurements, we showed that leptin is synthesized locally in the olfactory mucosa. In addition, we demonstrate that fasting causes a significant enhanced transcription of both leptin and Ob-Rs in rat OM by quantitative RT-PCR data. Altogether, these results strongly suggested that leptin, acting as an endocrine or a paracrine factor, could be an important regulator of olfactory function, as a neuromodulator of the olfactory message in cilia of mature olfactory receptors neurons (ORN), but also for the homeostasis of this complex tissue, acting on differentiating neurons and on sustentacular cells.

  16. Hormones

    MedlinePlus

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  17. Leptin as well as Free Leptin Receptor Is Associated with Polycystic Ovary Syndrome in Young Women

    PubMed Central

    Rizk, Nasser M.; Sharif, Elham

    2015-01-01

    Background and Aim. Leptin has two forms in the circulation: free and bound forms. The soluble leptin receptor (sOB-R) circulates in the blood and can bind to leptin. The aim of this study is to assess the concentrations of the leptin and the sOB-R in PCOS and its relation to adiposity, insulin resistance, and androgens. Methods. A cross-sectional study included 78 female students aged 17–25 years. Fasting serum leptin and sOB-R concentrations were measured. The anthropometric variables and the hormonal profile such as insulin, female and male sex hormones, and prolactin were assessed. Results. In PCOS, leptin level (ng/ml) and free leptin index (FLI) increased significantly while sOB-R (ng/ml) significantly decreased compared to control subjects. In age-matched subjects, obese PCOS had increased leptin level in ng/ml (median level with interquartile levels) of 45.67 (41.98–48.04) and decreased sOB-R in ng/ml 11.47 (7.59–16.44) compared to lean PCOS 16.97 (10.60–45.55) for leptin and 16.62 (11.61–17.96) for sOB-R with p values 0.013 and 0.042, respectively. However, body mass index (BMI) is significantly correlated with leptin and s-OBR, while no significant correlations with parameters of insulin resistance were detected. Conclusion. PCOS is associated with hyperleptinemia and increased free leptin index. Decreased sOB-R could be a compensatory mechanism for the defective action of leptin. PMID:26180527

  18. 75 FR 44274 - Prospective Grant of Exclusive License: Use of Leptin and Leptin Analogs for the Treatment of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-28

    ... leptin, a protein hormone that plays a key role in regulating energy intake and expenditure. This hormone is released from adipose tissue and inhibits appetite in the brain by counteracting peptide hormones responsible for stimulating hunger, and also stimulates the synthesis of another peptide hormone, -MSH,...

  19. Adipokines, hormones related to body composition, and insulin resistance in HIV fat redistribution syndrome

    PubMed Central

    2014-01-01

    Background Lipodystrophies are characterized by adipose tissue redistribution, insulin resistance (IR) and metabolic complications. Adipokines and hormones related to body composition may play an important role linking these alterations. Our aim was to evaluate adipocyte-derived hormones (adiponectin, leptin, resistin, TNF-α, PAI-1) and ghrelin plasma levels and their relationship with IR in HIV-infected patients according to the presence of lipodystrophy and fat redistribution. Methods Anthropometric and metabolic parameters, HOMA-IR, body composition by DXA and CT, and adipokines were evaluated in 217 HIV-infected patients on cART and 74 controls. Fat mass ratio defined lipodystrophy (L-FMR) was defined as the ratio of the percentage of the trunk fat mass to the percentage of the lower limb fat mass by DXA. Patient’s fat redistribution was classified into 4 different groups according the presence or absence of either clinical lipoatrophy or abdominal prominence: no lipodystrophy, isolated central fat accumulation (ICFA), isolated lipoatrophy and mixed forms (MXF). The associations between adipokines levels and anthropometric, metabolic and body composition were estimated by Spearman correlation. Results Leptin levels were lower in patients with FMR-L and isolated lipoatrophy, and higher in those with ICFA and MXF. Positive correlations were found between leptin and body fat (total, trunk, leg, arm fat evaluated by DXA, and total, visceral (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT ratio evaluated by CT) regardless of FMR-L, and with HOMA-IR only in patients with FMR-L. Adiponectin correlated negatively with VAT, and its mean levels were lower in patients with ICFA and higher in those with no lipodystrophy. Resistin was not correlated with adipose tissue but positively correlated with HOMA-IR in FMR-L patients. PAI-1 levels were higher in MXF-patients and their levels were positively correlated with VAT in those with FMR-L. Ghrelin was higher in HIV

  20. Leptin and its cardiovascular effects: Focus on angiogenesis

    PubMed Central

    Tahergorabi, Zoya; Khazaei, Majid

    2015-01-01

    Leptin is an endocrine hormone synthesized by adipocytes. It plays a key role in the energy homeostasis in central and peripheral tissues and has additional roles are attributed to it, such as the regulation of reproduction, immune function, bone homeostasis, and angiogenesis. The plasma concentration of leptin significantly increases in obese individuals. In the present review, we give an introduction concerning leptin, its receptors, signaling pathways, and its effect on cardiovascular system, especially on angiogenesis. PMID:26015905

  1. The role of leptin in central nervous system diseases

    PubMed Central

    Li, Xiao-Mei; Yan, Hai-Jing; Guo, Yi-Shan

    2016-01-01

    Leptin is a peptide hormone produced by adipose tissue and acts in brain centers to control critical physiological functions. Leptin receptors are especially abundant in the hypothalamus and trigger specific neuronal subpopulations, and activate several intracellular signaling events, including the JAK/STAT, MAPK, PI3K, and mTOR pathway. Although most studies focus on its role in energy intake and expenditure, leptin also plays a critical role in many central nervous system diseases. PMID:26885866

  2. Variation in plasma leptin-like immunoreactivity in free-living European starlings (Sturnus vulgaris)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leptin, a protein hormone secreted by fat cells, is best known for its role as an adiposity signal; however, leptin has diverse physiological roles ranging from regulation of feeding behavior and body weight, to effects on reproduction and immune function. Although leptin has been extensively studi...

  3. Free and total leptin serum levels and soluble leptin receptors levels in two models of genetic obesity: the Prader-Willi and the Down syndromes.

    PubMed

    Proto, Caterina; Romualdi, Daniela; Cento, Rosa Maria; Romano, Corrado; Campagna, Giuseppe; Lanzone, Antonio

    2007-08-01

    Alterations in energy balance and feeding behavior and the subsequent high frequency of obesity are hallmarks of 2 chromosomal diseases: the Prader-Willi syndrome (PWS) and the Down syndrome (DS). Leptin, an important regulator of food intake and energy homeostasis, circulates in 2 forms: a free, therefore active, fraction and a fraction bound to the soluble leptin receptor, whose bioavailability consequently participates in the regulation of leptin action. To investigate the possible role of the free-bound leptin balance in the pathogenesis of obesity in PWS and DS, we enrolled 7 obese women with DS, 5 obese women with PWS, 7 obese women, and 7 normal-weight healthy control women. Basal hormonal concentrations, total and free leptin levels, and leptin receptors levels were measured in plasma samples obtained from the 4 groups. No significant differences were observed in the hormonal milieu. Women with DS exhibited lower total leptin concentrations (P<.01), comparable leptin receptor level and, therefore, lower free leptin values (P<.01) when compared with obese controls, then resembling the profile peculiar to normal-weight control women. At variance, subjects with PWS did not differ from obese controls regarding both leptin and leptin receptor levels. Our data suggest that, whereas subjects with PWS have a leptin assessment corresponding to their degree of obesity, subjects with DS may have a defect in the secretion of leptin that could at least partially account for this form of syndromal obesity.

  4. Plasma leptin during reproduction in European Starlings (Sturnus vulgaris)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leptin, a systemic hormone produced by adipocytes or fat cells, has been widely studied in mammals, and is known to play diverse roles in body mass regulation, immune function, reproduction, etc. However we know very little about avian leptin, especially in free-living birds; indeed, this remains a ...

  5. Duplicated Leptin Receptors in Two Species of Eel Bring New Insights into the Evolution of the Leptin System in Vertebrates

    PubMed Central

    Morini, Marina; Pasquier, Jérémy; Dirks, Ron; van den Thillart, Guido; Tomkiewicz, Jonna; Rousseau, Karine; Dufour, Sylvie; Lafont, Anne-Gaëlle

    2015-01-01

    Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R. PMID:25946034

  6. Duplicated leptin receptors in two species of eel bring new insights into the evolution of the leptin system in vertebrates.

    PubMed

    Morini, Marina; Pasquier, Jérémy; Dirks, Ron; van den Thillart, Guido; Tomkiewicz, Jonna; Rousseau, Karine; Dufour, Sylvie; Lafont, Anne-Gaëlle

    2015-01-01

    Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R. PMID:25946034

  7. Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin.

    PubMed

    Matsuoka, N; Ogawa, Y; Masuzaki, H; Ebihara, K; Aizawa-Abe, M; Satoh, N; Ishikawa, E; Fujisawa, Y; Kosaki, A; Yamada, K; Kuzuya, H; Nakao, K

    2001-02-01

    Leptin is an adipocyte-derived circulating satiety factor with a variety of biological effects. Evidence has accumulated suggesting that leptin may modulate glucose and lipid metabolism. In the present study, we examined lipid metabolism in transgenic skinny mice with elevated plasma leptin concentrations. The plasma concentrations of triglycerides and free fatty acids in transgenic skinny mice were 71.5 (P < 0.01) and 89.1% (P < 0.05) of those in their nontransgenic littermates, respectively. Separation of plasma into lipoprotein classes by ultracentrifugation revealed that very low density lipoprotein-triglyceride concentrations were markedly reduced in transgenic skinny mice relative to the controls. The clearance of triglycerides estimated by a fat-loading test was enhanced in transgenic skinny mice; the triglyceride concentration in transgenic skinny mice 3 h after fat loading was 39.7% (P < 0.05) of that of their nontransgenic littermates. Postheparin plasma lipoprotein lipase activity increased 1.4-fold (P < 0.05) in transgenic skinny mice. Our data demonstrated a significant reduction in plasma triglyceride concentrations, accompanied by increased lipoprotein lipase activity in transgenic skinny mice overexpressing leptin, suggesting that leptin plays a role in long-term triglyceride metabolism.

  8. The thymoprotective function of leptin is indirectly mediated via suppression of obesity.

    PubMed

    Sreenivasan, Jayasree; Schlenner, Susan; Franckaert, Dean; Dooley, James; Liston, Adrian

    2015-09-01

    Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus.

  9. Evidence for leptin expression in fishes.

    PubMed

    Johnson, R M; Johnson, T M; Londraville, R L

    2000-06-01

    Tissues from bony fish were screened with anti-mouse leptin antibodies to detect the presence of the fat-regulating hormone in fishes. Low molecular-weight (16 kDa) immunoreactive bands were detected in blood, brain, heart and liver of green sunfish (Lepomis cyanellus), bluegill sunfish (Lepomis macrochirus), largemouth bass (Micropterus salmoides), white crappie (Pomonix annularis), channel catfish (Ictalurus punctatus), and rainbow trout (Oncorhynchus mykiss). To further verify that we had identified leptin, the response of fish "leptin" was measured in fed and fasted green sunfish. Fed sunfish had approximately threefold higher concentration of leptin in blood than did fasted sunfish (fed vs. fasted; 0.599 +/- 0.03 microg/microl vs. 0.196 +/- 0.04 microg/microl; P > F = 0.0001), which is consistent with mammalian models of leptin function. Brain leptin concentration is also positively correlated with percent body fat in white crappie and bluegill. Based upon electrophoretic mobility, immunoreactivity, response to fasting, and correlation with adiposity, we believe we have the first evidence for leptin expression in an ectotherm.

  10. Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.

    PubMed

    Masuzaki, H; Ogawa, Y; Aizawa-Abe, M; Hosoda, K; Suga, J; Ebihara, K; Satoh, N; Iwai, H; Inoue, G; Nishimura, H; Yoshimasa, Y; Nakao, K

    1999-08-01

    Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.

  11. The molecular clock mediates leptin-regulated bone formation.

    PubMed

    Fu, Loning; Patel, Millan S; Bradley, Allan; Wagner, Erwin F; Karsenty, Gerard

    2005-09-01

    The hormone leptin is a regulator of bone remodeling, a homeostatic function maintaining bone mass constant. Mice lacking molecular-clock components (Per and Cry), or lacking Per genes in osteoblasts, display high bone mass, suggesting that bone remodeling may also be subject to circadian regulation. Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion. Thus, clock genes may mediate the leptin-dependent sympathetic regulation of bone formation. We show that expression of clock genes in osteoblasts is regulated by the sympathetic nervous system and leptin. Clock genes mediate the antiproliferative function of sympathetic signaling by inhibiting G1 cyclin expression. Partially antagonizing this inhibitory loop, leptin also upregulates AP-1 gene expression, which promotes cyclin D1 expression, osteoblast proliferation, and bone formation. Thus, leptin determines the extent of bone formation by modulating, via sympathetic signaling, osteoblast proliferation through two antagonistic pathways, one of which involves the molecular clock.

  12. Leptin, 20 years of searching for glucose homeostasis.

    PubMed

    Fernández-Formoso, Gabriela; Pérez-Sieira, Sonia; González-Touceda, David; Dieguez, Carlos; Tovar, Sulay

    2015-11-01

    Leptin was discovered in 1994 (20 years ago). In addition to having well-characterized effects on the regulation of energy homeostasis, leptin clearly also plays a major role in metabolic homeostasis. In fact, leptin plays an important role in the regulation of glucose homeostasis independent of food intake and body weight. The mechanism underlying the modulation of glucose metabolism by leptin is not completely understood, although evidence indicates that the effect occurs at both the central and peripheral levels. In this review, we will focus on the role of leptin in glucose homeostasis at the central level and its role in insulin secretion and in counteracting hormones, such as glucagon, growth hormone, cortisol and catecholamines.

  13. Circulating Leptin and Pain Perception among Tobacco Dependent Individuals

    PubMed Central

    al’Absi, Mustafa; Lemieux, Andrine; Nakajima, Motohiro; Hatsukami, Dorothy K.; Allen, Sharon

    2015-01-01

    Recent preclinical evidence suggests that leptin may modulate the stress response and may increase nociception. In this study, we examined for the first time the extent to which cigarette smoking is associated with leptin levels during an extended rest period and in response to noxious stimuli. Repeated blood samples were collected during a laboratory session from smokers and nonsmokers and assayed for leptin. Pain experiences, as well as neuroendocrine and cardiovascular measures, were collected across cold pressor and thermal heat pain tests. Both analysis of variance and correlations confirmed that smokers demonstrated dysregulations in leptin responsivity and association with pain relative to nonsmokers. The flat pattern of leptin release and the weak associations of this hormone with pain in smokers suggest a long-term effect of tobacco dependence on this regulatory hormone. In light of leptin’s influence on reward pathways, further investigation of leptin’s involvement in nicotine dependence is warranted. PMID:25720946

  14. Association of Leptin with Body Pain in Women

    PubMed Central

    Kapphahn, Kristopher; Brennan, Kathleen; Sullivan, Shannon D.; Stefanick, Marcia L.

    2016-01-01

    Abstract Leptin, an appetite-regulatory hormone, is also known to act as a proinflammatory adipokine. One of the effects of increased systemic leptin concentrations may be greater sensitivity to pain. We report the results of two studies examining the association between leptin and pain: a small pilot longitudinal study, followed by a large cross-sectional study. In Study 1, three women with physician-diagnosed fibromyalgia provided blood draws daily for 25 consecutive days, as well as daily self-reported musculoskeletal pain. Daily fluctuations in serum leptin were positively associated with pain across all three participants (F (1,63) = 12.8, p < 0.001), with leptin predicting ∼49% of the pain variance. In Study 2, the relationship between leptin and body pain was examined in a retrospective cross-sectional analysis of 5676 generally healthy postmenopausal women from the Women's Health Initiative. Leptin levels obtained from single blood draws were tested for a relationship with self-reported body pain. Body mass index (BMI) was also included as a predictor of pain. Both leptin and BMI were found to be independently associated with self-reported pain (p = 0.001 and p < 0.001, respectively), with higher leptin levels and greater BMI each being associated with greater pain. Leptin appears to be a predictor of body pain both within- and between-individuals and may be a driver of generalized pain states such as fibromyalgia. PMID:27028709

  15. Leptin's effect on taste bud calcium responses and transmitter secretion.

    PubMed

    Meredith, Tricia L; Corcoran, Alan; Roper, Stephen D

    2015-05-01

    Leptin, a peptide hormone released by adipose tissue, acts on the hypothalamus to control cravings and appetite. Leptin also acts to decrease taste responses to sweet substances, though there is little detailed information regarding where leptin acts in the taste transduction cascade. The present study examined the effects of leptin on sweet-evoked responses and neuro transmitter release from isolated taste buds. Our results indicate that leptin moderately decreased sweet-evoked calcium mobilization in isolated mouse taste buds. We also employed Chinese hamster ovary biosensor cells to examine taste transmitter release from isolated taste buds. Leptin reduced ATP and increased serotonin release in response to sweet stimulation. However, leptin has no effect on bitter-evoked transmitter release, further showing that the action of leptin is sweet specific. Our results support those of previous studies, which state that leptin acts on taste tissue via the leptin receptor, most likely on Type II (Receptor) cells, but also possibly on Type III (Presynaptic) cells.

  16. Leptin's effect on taste bud calcium responses and transmitter secretion.

    PubMed

    Meredith, Tricia L; Corcoran, Alan; Roper, Stephen D

    2015-05-01

    Leptin, a peptide hormone released by adipose tissue, acts on the hypothalamus to control cravings and appetite. Leptin also acts to decrease taste responses to sweet substances, though there is little detailed information regarding where leptin acts in the taste transduction cascade. The present study examined the effects of leptin on sweet-evoked responses and neuro transmitter release from isolated taste buds. Our results indicate that leptin moderately decreased sweet-evoked calcium mobilization in isolated mouse taste buds. We also employed Chinese hamster ovary biosensor cells to examine taste transmitter release from isolated taste buds. Leptin reduced ATP and increased serotonin release in response to sweet stimulation. However, leptin has no effect on bitter-evoked transmitter release, further showing that the action of leptin is sweet specific. Our results support those of previous studies, which state that leptin acts on taste tissue via the leptin receptor, most likely on Type II (Receptor) cells, but also possibly on Type III (Presynaptic) cells. PMID:25537017

  17. Regulation of leptin mRNA and protein expression in pituitary somatotropes.

    PubMed

    McDuffie, Iris A; Akhter, Noor; Childs, Gwen V

    2004-02-01

    Leptin, the ob protein, regulates food intake and satiety and can be found in the anterior pituitary. Leptin antigens and mRNA were studied in the anterior pituitary (AP) cells of male and female rats to learn more about its regulation. Leptin antigens were found in over 40% of cells in diestrous or proestrous female rats and in male rats. Lower percentages of AP cells were seen in the estrous population (21 +/- 7%). During peak expression of antigens, co-expression of leptin and growth hormone (GH) was found in 27 +/- 4% of AP cells. Affinity cytochemistry studies detected 24 +/- 3% of AP cells with leptin proteins and growth hormone releasing hormone (GHRH) receptors. These data suggested that somatotropes were a significant source of leptin. To test regulatory factors, estrous and diestrous AP populations were treated with estrogen (100 pM) and/or GHRH (2 nM) to learn if either would increase leptin expression in GH cells. To rule out the possibility that the immunoreactive leptin was bound to receptors in somatotropes, leptin mRNA was also detected by non-radioactive in situ hybridization in this group of cells. In estrous female rats, 39 +/- 0.9% of AP cells expressed leptin mRNA, indicating that the potential for leptin production was greater than predicted from the immunolabeling. Estrogen and GHRH together (but not alone) increased percentages of cells with leptin protein (41 +/- 9%) or mRNA (57 +/- 5%). Estrogen and GHRH also increased the percentages of AP cells that co-express leptin mRNA and GH antigens from 20 +/- 2% of AP cells to 37 +/- 5%. Although the significance of leptin in GH cells is not understood, it is clearly increased after stimulation with GHRH and estrogen. Because GH cells also have leptin receptors, this AP leptin may be an autocrine or paracrine regulator of pituitary cell function.

  18. Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease.

    PubMed

    Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; D'Angiulli, Amedeo; Rodríguez-Díaz, Joel; Blaurock-Busch, Eleonore; Busch, Yvette; Chao, Chih-kai; Thompson, Charles; Mukherjee, Partha S; Torres-Jardón, Ricardo; Perry, George

    2015-07-01

    Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer

  19. Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease.

    PubMed

    Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; D'Angiulli, Amedeo; Rodríguez-Díaz, Joel; Blaurock-Busch, Eleonore; Busch, Yvette; Chao, Chih-kai; Thompson, Charles; Mukherjee, Partha S; Torres-Jardón, Ricardo; Perry, George

    2015-07-01

    Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer

  20. Leptins and leptin receptor expression in the goldfish (Carassius auratus). Regulation by food intake and fasting/overfeeding conditions.

    PubMed

    Tinoco, Ana Belén; Nisembaum, Laura Gabriela; Isorna, Esther; Delgado, María Jesús; de Pedro, Nuria

    2012-04-01

    Leptin is a hormone involved in feeding and body weight regulation in vertebrates, but the relationship between energy status and leptin has not been clearly established in fish. The aim of this study was to investigate in a teleost, the goldfish (Carassius auratus), the tissue expression pattern of two leptins (gLep-aI and gLep-aII) and leptin receptor (gLepR); and the effect of feeding on expression of these genes. Leptin system expression in goldfish was firstly analyzed in fish under overfeeding (2 weeks) or fasting (1 week), and secondly, at different postfeeding times (0, 3, 6, 9 and 12h). Goldfish has two Lep-a paralog genes, gLep-aI was widely expressed in central and peripheral tissues, whereas gLep-aII was preferentially expressed in brain. This different distribution pattern of leptins suggests that they can play different physiological roles in goldfish. The gLepR mRNA was ubiquitous expressed, with the highest expression in the telencephalon and hypothalamus. No significant differences in the leptin system expression were found among control, overfed and fasting groups, suggesting an apparent lack of correlation between nutritional status and leptin system in goldfish. Hepatic expression of gLep-aI significantly increased 9h after feeding time, while hypothalamic leptin system expression did not change after feeding. In summary, leptin in goldfish could signal short-term changes in food intake, as postprandial satiety, but seems to be independent of fasting/overfeeding conditions in this teleost. The widespread distribution of leptins and leptin receptor in goldfish strongly supports that this hormone may have pleitropic actions in fish.

  1. Circulating ghrelin and leptin concentrations and growth hormone secretagogue receptor abundance in liver, muscle, and adipose tissue of beef cattle exhibiting differences in composition of gain.

    PubMed

    Jennings, J S; Wertz-Lutz, A E; Pritchard, R H; Weaver, A D; Keisler, D H; Bruns, K

    2011-12-01

    Data from species other than cattle indicate that ghrelin and GH secretagogue receptor (GHS-R) could play a key role in fat deposition, energy homeostasis, or glucose metabolism by directly affecting liver and adipose tissue metabolism. Beef steers (n = 72) were used to test the hypothesis that plasma ghrelin and leptin concentrations and abundance of the GHS-R in liver, muscle, and adipose tissues differ in steers exhibiting differences in composition of gain. At trial initiation (d 0), 8 steers were slaughtered for initial carcass composition. The remaining 64 steers were stratified by BW, allotted to pen, and treatment was assigned randomly to pen. Steers were not implanted with anabolic steroids. Treatments were 1) a low-energy (LE) diet fed during the growing period (0 to 111 d) followed by a high-energy (HE) diet during the finishing period (112 to 209 d; LE-HE) or 2) the HE diet for the duration of the trial (1 to 209 d; HE-HE). Eight steers per treatment were slaughtered on d 88, 111, 160, and 209. Carcass ninth, tenth, and eleventh rib sections were dissected for chemical composition and regression equations were developed to predict compositional gain. Liver, muscle, and subcutaneous adipose tissues were frozen in liquid nitrogen for subsequent Western blotting for GHS-R. Replicate blood samples collected before each slaughter were assayed for ghrelin and leptin concentrations. When compared at a common compositional fat end-point, the rate of carcass fat accretion (g·kg of shrunk BW(-1)) was greater (P < 0.001) in HE-HE steers whereas the rate of carcass protein accretion (g·kg of shrunk BW(-1)) was less (P < 0.001) compared with LE-HE steers. When compared at a common compositional fat end-point, plasma leptin, ghrelin, and insulin concentrations were greater (P < 0.05) for HE-HE compared with LE-HE steers. Abundance of the GHS-R, to which ghrelin binds, increased over time in liver and adipose tissue but did not differ as a result of treatment

  2. Leptin regulation of neuronal morphology and hippocampal synaptic function

    PubMed Central

    Harvey, Jenni

    2013-01-01

    The central actions of the hormone leptin in regulating energy homeostasis via the hypothalamus are well documented. However, evidence is growing that this hormone can also modify the structure and function of synapses throughout the CNS. The hippocampus is a region of the forebrain that plays a crucial role in associative learning and memory and is an area also highly vulnerable to neurodegenerative processes. Recent studies indicate that leptin is a potential cognitive enhancer as it modulates the cellular processes underlying hippocampal-dependent learning and memory including dendritic morphology, glutamate receptor trafficking and activity-dependent synaptic plasticity. Here, we review the recent evidence implicating the hormone leptin as a key regulator of hippocampal synaptic function and discuss the role of leptin receptor-driven lipid signaling pathways involved in this process. PMID:23964236

  3. Expression of leptin and its receptors in various tissues of ruminants.

    PubMed

    Bartha, T; Sayed-Ahmed, A; Rudas, P

    2005-07-01

    The energy metabolism of domestic animals is under the control of hormonal factors, which include thyroid hormones and leptin. Leptin signals from the periphery to the centre. It is mostly produced in the white adipose tissue and informs the central nervous system (CNS) about the total fat depot of the body. Low and high levels of leptin induce anabolic and catabolic processes, respectively. Besides controlling the food uptake and energy expenditure leptin is also involved in regulation of the reproduction and the immune system. Leptin is produced in several tissues other than fat. In the present paper the leptin expression of ruminant (Egyptian water buffalo, cow, and one-humped camel) tissues are examined. The mammary gland produces leptin in each species investigated. The local hormone production contributes to milk leptin and most probably helps to maintain lactation. Considerable leptin receptor expression was observed in the milk-producing epithelial cells, which is the same cell type that produces most of the udder leptin. Based on the results tissues participating in production have an autoregulative mechanism through which tissues can be relatively independent of the plasma leptin levels in order to maintain the desired function.

  4. Sex Differences in Somatotrope Dependency on Leptin Receptors in Young Mice: Ablation of LEPR Causes Severe Growth Hormone Deficiency and Abdominal Obesity in Males.

    PubMed

    Allensworth-James, Melody L; Odle, Angela; Haney, Anessa; Childs, Gwen

    2015-09-01

    Leptin receptor (LEPR) signaling controls appetite and energy expenditure. Somatotrope-specific deletion of the LEPRb signaling isoform causes GH deficiency and obesity. The present study selectively ablated Lepr exon 1 in somatotropes, which removes the signal peptide, causing the loss of all isoforms of LEPR. Excision of Lepr exon 1 was restricted to the pituitary, and mutant somatotropes failed to respond to leptin. Young (2-3 mo) males showed a severe 84% reduction in serum GH levels and more than 60% reduction in immunolabeled GH cells compared with 41%-42% reductions in GH and GH cells in mutant females. Mutant males (35 d) and females (45 d) weighed less than controls and males had lower lean body mass. Image analysis of adipose tissue by magnetic resonance imaging showed that young males had a 2-fold increase in abdominal fat mass and increased adipose tissue density. Young females had only an overall increase in adipose tissue. Both males and females showed lower energy expenditure and higher respiratory quotient, indicating preferential carbohydrate burning. Young mutant males slept less and were more restless during the dark phase, whereas the opposite was true of females. The effects of a Cre-bearing sire on his non-Cre-recombinase bearing progeny are seen by increased respiratory quotient and reduced litter sizes. These studies elucidate clear sex differences in the extent to which somatotropes are dependent on all isoforms of LEPR. These results, which were not seen with the ablation of Lepr exon 17, highlight the severe consequences of ablation of LEPR in male somatotropes. PMID:26168341

  5. Leptin as an uremic toxin: Deleterious role of leptin in chronic kidney disease.

    PubMed

    Alix, Pascaline M; Guebre-Egziabher, Fitsum; Soulage, Christophe O

    2014-10-01

    White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD.

  6. Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.

    PubMed

    Zabeau, Lennart; Jensen, Cathy J; Seeuws, Sylvie; Venken, Koen; Verhee, Annick; Catteeuw, Dominiek; van Loo, Geert; Chen, Hui; Walder, Ken; Hollis, Jacob; Foote, Simon; Morris, Margaret J; Van der Heyden, José; Peelman, Frank; Oldfield, Brian J; Rubio, Justin P; Elewaut, Dirk; Tavernier, Jan

    2015-02-01

    The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions. PMID:25098352

  7. The role of leptin in reproduction: experimental and clinical aspects.

    PubMed

    Baldelli, Roberto; Dieguez, Carlos; Casanueva, Felipe F

    2002-01-01

    The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and future treatment as well as our understanding of energy homeostasis in man. In addition to its relevant role as a metabolic adaptor to overweight and fasting states, new and previously unsuspected neuroendocrinological roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation and appears as a permissive factor for puberty. In particular, various sets of data suggest that leptin may serve as a signal to the central nervous system (CNS) with information on the critical amount of adipose tissue stores that is necessary for gonadotropin-releasing hormone (GnRH) secretion and pubertal activation of the hypothalamic-pituitary-gonadal axis. Leptin also acts at the periphery, directly on the ovary and testis where it may control steroidogenesis, although the exact role of intragonadal action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated. Furthermore, relevant gender-based differences in leptin levels exist, with higher levels in women, even at birth, and which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the menstrual cycle, with a regulatory role exerted at hypothalamic, pituitary and gonadal levels, and with severe changes in pregnancy and postpartum. Moreover, leptin is present in both human and commercial milk, and may play a role in the adaptive responses of the newborn.

  8. Leptin suppresses sweet taste responses of enteroendocrine STC-1 cells.

    PubMed

    Jyotaki, Masafumi; Sanematsu, Keisuke; Shigemura, Noriatsu; Yoshida, Ryusuke; Ninomiya, Yuzo

    2016-09-22

    Leptin is an important hormone that regulates food intake and energy homeostasis by acting on central and peripheral targets. In the gustatory system, leptin is known to selectively suppress sweet responses by inhibiting the activation of sweet sensitive taste cells. Sweet taste receptor (T1R2+T1R3) is also expressed in gut enteroendocrine cells and contributes to nutrient sensing, hormone release and glucose absorption. Because of the similarities in expression patterns between enteroendocrine and taste receptor cells, we hypothesized that they may also share similar mechanisms used to modify/regulate the sweet responsiveness of these cells by leptin. Here, we used mouse enteroendocrine cell line STC-1 and examined potential effect of leptin on Ca(2+) responses of STC-1 cells to various taste compounds. Ca(2+) responses to sweet compounds in STC-1 cells were suppressed by a rodent T1R3 inhibitor gurmarin, suggesting the involvement of T1R3-dependent receptors in detection of sweet compounds. Responses to sweet substances were suppressed by ⩾1ng/ml leptin without affecting responses to bitter, umami and salty compounds. This effect was inhibited by a leptin antagonist (mutant L39A/D40A/F41A) and by ATP gated K(+) (KATP) channel closer glibenclamide, suggesting that leptin affects sweet taste responses of enteroendocrine cells via activation of leptin receptor and KATP channel expressed in these cells. Moreover, leptin selectively inhibited sweet-induced but not bitter-induced glucagon-like peptide-1 (GLP-1) secretion from STC-1 cells. These results suggest that leptin modulates sweet taste responses of enteroendocrine cells to regulate nutrient sensing, hormone release and glucose absorption in the gut. PMID:27353597

  9. Leptin mRNA expresses in the bull reproductive organ.

    PubMed

    Abavisani, A; Baghbanzadeh, A; Shayan, P; Tajik, P; Dehghani, H; Mirtorabi, M

    2009-12-01

    Leptin, a 167-amino acid hormone, is secreted mainly by fat tissue. It has some powerful effects on the regulation of metabolism and reproductive function through endocrine and probably paracrine mechanisms. The contribution rate of leptin function on the male reproductive system is not still clear. Characterization of leptin expression in reproductive organs will suggest that in addition to its endocrine action, leptin has also paracrine/autocrine effects on reproduction. The expression of functional leptin receptor mRNA has been already recognized in testis of rodents, human and cattle. Thus, the aim of the present study was to investigate the presence of leptin mRNA in the bovine testis, because it will be the first step for understanding of its paracrine/autocrine effects on the male reproductive organs in cattle. The present study was the first to showed leptin mRNA expression in the testis of Holstein cattle using reverse transcription and polymerase chain reaction (RT-PCR) analysis. RT-PCR products were amplified with nested PCR using inner leptin primer pairs to emphasis the first results. Besides, bovine beta actin gene was acted as an internal positive control as well as RNA purification marker. Our findings suggest that in addition to its endocrine actions at the hypothalamic-pituitary axis, leptin can has an autocrine and/or paracrine role in bull testicular function.

  10. Partial cloning and localization of leptin and leptin receptor in the mammary gland of the Egyptian water buffalo.

    PubMed

    Sayed-Ahmed, A; Elmorsy, S Elm; Rudas, P; Bartha, T

    2003-10-01

    Originally an overall metabolic control was attributed to the leptin hormone, which is produced mainly by the adipose tissue. Recently, leptin gene expression was demonstrated in several additional peripheral tissues. Furthermore, several isoforms of leptin receptor were found both in the central nervous system and in the peripheral tissues. Using reverse transcription and polymerase chain reaction analysis we demonstrate that leptin is expressed both in the adipose tissue and in the lactating mammary gland tissue of Egyptian water buffalo. Our results show that, short and long isoforms of leptin receptor are expressed in buffalo mammary gland tissue. We have partially cloned the buffalo leptin and its short and long isoforms of receptor, which show a high sequence homology to previously published sequences of other mammalian species especially to that of other ruminants. Localization of leptin and its receptor mRNA transcripts, as determined by in situ hybridization procedure, revealed that leptin and its receptor transcripts are expressed specifically in the alveolar epithelial cells of the mammary gland. These morphological data support that leptin could also act as an autocrine and paracrine mediator for mammary gland metabolism and as a facilitator of alveolar epithelial cell activity during lactation.

  11. Identification of targets of leptin action in rat hypothalamus.

    PubMed Central

    Schwartz, M W; Seeley, R J; Campfield, L A; Burn, P; Baskin, D G

    1996-01-01

    The hypothesis that leptin (OB protein) acts in the hypothalamus to reduce food intake and body weight is based primarily on evidence from leptin-deficient, ob/ob mice. To investigate whether leptin exerts similar effects in normal animals, we administered leptin intracerebroventricularly (icv) to Long-Evans rats. Leptin administration (3.5 microg icv) at the onset of nocturnal feeding reduced food intake by 50% at 1 h and by 42% at 4 h, as compared with vehicle-treated controls (both P < 0.05). To investigate the basis for this effect, we used in situ hybridization (ISH) to determine whether leptin alters expression of hypothalamic neuropeptides involved in energy homeostasis. Two injections of leptin (3.5 microg icv) during a 40 h fast significantly decreased levels of mRNA for neuropeptide Y (NPY, which stimulates food intake) in the arcuate nucleus (-24%) and increased levels of mRNA for corticotrophin releasing hormone (CRH, an inhibitor of food intake) in the paraventricular nucleus (by 38%) (both P < 0.05 vs. vehicle-treated controls). To investigate the anatomic basis for these effects, we measured leptin receptor gene expression in rat brain by ISH using a probe complementary to mRNA for all leptin receptor splice variants. Leptin receptor mRNA was densely concentrated in the arcuate nucleus, with lower levels present in the ventromedial and dorsomedial hypothalamic nuclei and other brain areas involved in energy balance. These findings suggest that leptin action in rat hypothalamus involves altered expression of key neuropeptide genes, and implicate leptin in the hypothalamic response to fasting. PMID:8787671

  12. PET imaging of leptin biodistribution and metabolism in rodents and primates.

    PubMed

    Ceccarini, Giovanni; Flavell, Robert R; Butelman, Eduardo R; Synan, Michael; Willnow, Thomas E; Bar-Dagan, Maya; Goldsmith, Stanley J; Kreek, Mary J; Kothari, Paresh; Vallabhajosula, Shankar; Muir, Tom W; Friedman, Jeffrey M

    2009-08-01

    We have determined the systemic biodistribution of the hormone leptin by PET imaging. PET imaging using (18)F- and (68)Ga-labeled leptin revealed that, in mouse, the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys, 15% of labeled leptin localized to red bone marrow, which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showing that leptin modulates immune function. These experiments set the stage for similar studies in humans to assess the extent to which alterations of leptin's biodistribution might contribute to obesity; they also provide a general chemical strategy for (18)F labeling of proteins for PET imaging of other polypeptide hormones.

  13. Leptin (ob gene) of the South African clawed frog Xenopus laevis

    PubMed Central

    Crespi, Erica J.; Denver, Robert J.

    2006-01-01

    Leptin, the protein product of the obese (ob) gene, is a type-I cytokine hormone secreted by fat that is integral to food intake regulation and influences almost every physiological system in juvenile and adult mammals. Since the identification of leptin in the mouse in 1994, biologists have searched for orthologous genes in other species with limited success. In this article, we report the identification and functional characterization of leptin and leptin receptor (LR) in Xenopus. Despite low amino acid sequence similarity to mammalian leptins (≈35%) the frog protein has a nearly identical predicted tertiary structure and can activate the frog and mouse LRs in vitro. We showed that recombinant frog leptin (rxLeptin) is a potent anorexigen in frogs, as it is in mammals, but this response does not develop until midprometamorphosis. However, during early prometamorphosis, exogenous rxLeptin induced growth and development of the hind limb, where LR mRNA is expressed. The rxLeptin also stimulated cell proliferation in cultured hind limbs from early prometamorphic tadpoles, as measured by [3H]thymidine uptake. These findings are evidence that leptin can influence limb growth and differentiation during early development. Furthermore, the isolation and characterization of leptin and its receptor in a nonamniote provides an essential foundation for elucidating the structural and functional evolution of this important hormone. PMID:16782821

  14. Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause

    PubMed Central

    Rył, Aleksandra; Jasiewicz, Andrzej; Grzywacz, Anna; Adler, Grażyna; Skonieczna-Żydecka, Karolina; Rotter, Iwona; Sipak-Szmigiel, Olimpia; Rumianowski, Bogdan; Karakiewicz, Beata; Jurczak, Anna; Parczewski, Miłosz; Urbańska, Anna; Grabowska, Marta; Laszczyńska, Maria

    2016-01-01

    Background: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman’s body after menopause and different genetic variants are still being sought. Methods: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE) and lepitn (LEP) genotypes were determined by real-time PCR and polymerase chain reaction–restriction fragment length polymorphism, respectively. Results: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. Conclusions: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels. PMID:27240396

  15. Leptin and puberty.

    PubMed

    Urbanski, H F

    2001-12-01

    Leptin is thought to relay metabolic information to the hypothalamic-pituitary- gonadal axis and to participate in the neuroendocrine control of puberty. To help elucidate the underlying mechanism, Cheung et al. recently performed a diverse series of experiments, the results of which undermine the prevailing hypothesis that leptin acts as a metabolic trigger for the initiation of puberty. Instead, their results suggest that leptin is one of many permissive metabolic factors that allow pubertal development to proceed.

  16. Leptin and Inflammation

    PubMed Central

    Iikuni, Noriko; Lam, Queenie Lai Kwan; Lu, Liwei; Matarese, Giuseppe; La Cava, Antonio

    2009-01-01

    The past few years of research on leptin have provided important information on the link between metabolism and immune homeostasis. Adipocytes influence not only the endocrine system but also the immune response through several cytokine-like mediators known as adipokines, which include leptin. It is widely accepted that leptin can directly link nutritional status and pro-inflammatory T helper 1 immune responses, and that a decrease of leptin plasma concentration during food deprivation can lead to an impaired immune function. Additionally, several studies have implicated leptin in the pathogenesis of chronic inflammation, and the elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. Conversely, reduced levels of leptin such as those found in malnourished individuals have been linked to increased risk of infection and reduced cell-mediated immune responses. We discuss here the functional influences of leptin in the physiopathology of inflammation, and the effects of leptin in the modulation of such responses. PMID:20198122

  17. Leptin in congenital and HIV-associated lipodystrophy.

    PubMed

    Tsoukas, Michael A; Farr, Olivia M; Mantzoros, Christos S

    2015-01-01

    Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy.

  18. Plasma Leptin Levels in Children Hospitalized with Cholera in Bangladesh.

    PubMed

    Falkard, Brie; Uddin, Taher; Rahman, M Arifur; Franke, Molly F; Aktar, Amena; Uddin, Muhammad Ikhtear; Bhuiyan, Taufiqur Rahman; Leung, Daniel T; Charles, Richelle C; Larocque, Regina C; Harris, Jason B; Calderwood, Stephen B; Qadri, Firdausi; Ryan, Edward T

    2015-08-01

    Vibrio cholerae, the cause of cholera, induces both innate and adaptive immune responses in infected humans. Leptin is a hormone that plays a role in both metabolism and mediating immune responses. We characterized leptin levels in 11 children with cholera in Bangladesh, assessing leptin levels on days 2, 7, 30, and 180 following cholera. We found that patients at the acute stage of cholera had significantly lower plasma leptin levels than matched controls, and compared with levels in late convalescence. We then assessed immune responses to V. cholerae antigens in 74 children with cholera, correlating these responses to plasma leptin levels on day 2 of illness. In multivariate analysis, we found an association between day 2 leptin levels and development of later anti-cholera toxin B subunit (CtxB) responses. This finding appeared to be limited to children with better nutritional status. Interestingly, we found no association between leptin levels and antibody responses to V. cholerae lipopolysaccharide, a T cell-independent antigen. Our results suggest that leptin levels may be associated with cholera, including the development of immune responses to T cell-dependent antigens.

  19. Development of Dissociation-Enhanced Lanthanide Fluoroimmunoassay for Measuring Leptin.

    PubMed

    Kim, Namsoo; Son, So-Hee

    2016-09-01

    Development of a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) for measuring leptin, a satiety hormone of appetite control, was conducted in sandwich assay format exploiting a microplate immobilized with an anti-leptin antibody and another antibody raised against leptin and tagged with an europium chelate. In the leptin DELFIA of this study, amounts of antibody coated to the microplate and of the bioconjugate for the second immune reaction were optimized as 0.5 μg and 200 ng per well, respectively. When plotted in double-logarithmic scale, a linear relationship of y (log10 response signal) = 0.6023× (log10 leptin concentration) + 3.4084 (r(2) = 0.9646) was obtained at the leptin concentrations of 0.01─50 ng/mL with the limit of detection of 0.01 ng/mL. Individual leptin concentrations in various samples were well convergent to the calibration curve of the current assay. When applied to the measurement of leptin in a rat serum, the present assay was found quite effective and was competitive to a commercial sandwich-type ELISA. PMID:27343179

  20. Differential Role of Leptin and Adiponectin in Cardiovascular System

    PubMed Central

    Ghantous, C. M.; Azrak, Z.; Hanache, S.; Abou-Kheir, W.; Zeidan, A.

    2015-01-01

    Leptin and adiponectin are differentially expressed adipokines in obesity and cardiovascular diseases. Leptin levels are directly associated with adipose tissue mass, while adiponectin levels are downregulated in obesity. Although significantly produced by adipocytes, leptin is also produced by vascular smooth muscle cells and cardiomyocytes. Plasma leptin concentrations are elevated in cases of cardiovascular diseases, such as hypertension, congestive heart failure, and myocardial infarction. As for the event of left ventricular hypertrophy, researchers have been stirring controversy about the role of leptin in this form of cardiac remodeling. In this review, we discuss how leptin has been shown to play an antihypertrophic role in the development of left ventricular hypertrophy through in vitro experiments, population-based cross-sectional studies, and longitudinal cohort studies. Conversely, we also examine how leptin may actually promote left ventricular hypertrophy using in vitro analysis and human-based univariate and multiple linear stepwise regression analysis. On the other hand, as opposed to leptin's generally detrimental effects on the cardiovascular system, adiponectin is a cardioprotective hormone that reduces left ventricular and vascular hypertrophy, oxidative stress, and inflammation. In this review, we also highlight adiponectin signaling and its protective actions on the cardiovascular system. PMID:26064110

  1. Modulation of intestinal L-glutamate transport by luminal leptin.

    PubMed

    Fanjul, Carmen; Barrenetxe, Jaione; Lostao, María Pilar; Ducroc, Robert

    2015-06-01

    Leptin is secreted into the digestive tract and contributes to the absorption of dietary molecules by regulating transporters activity. Here, we studied the effect of luminal leptin on the intestinal transport of L-glutamate, an important component of human diet. We examined the effect of leptin on L-glutamate uptake in rat intestine in vitro measuring glutamate-induced short-circuit current (Isc) in Ussing chambers and L-[(3)H (U)]-glutamate uptake in jejunal everted rings. Glutamate-induced Isc was only observed in Na(+)-free conditions. This Isc was concentration (1-60 mmol L(-1)) and pH dependent. Luminal leptin increased glutamate Isc (∼100 %). Dose-response curve showed a biphasic pattern, with maximal stimulations observed at 10(-13) and 10(-10) mmol L(-1), that were sensitive to leptin receptor antagonist. In everted rings, two glutamate transport mechanisms were distinguished: a Na(+)-dependent, H(+)-independent, that was inhibited by leptin (∼20 %), and a Na(+)-independent but H(+)-dependent, that was enhanced by leptin (∼20 %), in line with data obtained in Ussing chambers. Altogether, these data reveal original non-monotonic effect of luminal leptin in the intestine and demonstrate a new role for this hormone in the modulation of L-glutamate transport, showing that luminal active gut peptides can influence absorption of amino acids.

  2. Effects of long-term restricted feeding on plasma leptin, hepatic leptin expression and leptin receptor expression in juvenile Atlantic salmon (Salmo salar L.).

    PubMed

    Trombley, Susanne; Maugars, Gersende; Kling, Peter; Björnsson, Björn Thrandur; Schmitz, Monika

    2012-01-01

    Leptin is a pleiotropic hormone and plays a key role in body weight regulation, energy homeostasis and lipid store utilization in mammals. In this study, we investigated the effect of feed-restriction on leptin genes (lepa1 and lepa2), leptin receptor (lepr) gene expression and plasma leptin levels in juvenile Atlantic salmon parr. Feed restriction was performed from late April to mid-June, in order to gain insight into the role of the leptin system in energy balance regulation and adiposity in juvenile salmon. A significant increase in lepa1 expression as well as higher levels of plasma leptin was found in feed-restricted fish in June compared to fully fed controls, while lepa2 gene expression decreased in both groups during the treatment period. Lepa2 was, however significantly higher in the feed-restricted group in June. Leptin receptor expression was up regulated during the period of enhanced growth and lipid deposition in the fully fed control, indicating a seasonal effect on the receptor expression in the brain. Both lepa1 and lepa2 genes very mainly expressed in the liver in juvenile salmon, while lepr was expressed in the brain but showed also considerable expression in various peripheral tissues. The study provides evidence that the leptin system is sensitive to the metabolic status of the fish as both season and restricted feeding affect lepa1 and lepa2 gene expression in the liver and brain leptin receptor expression, however, for lepa1 expression and leptin plasma level in an opposite way as that observed in the mammalian system.

  3. Possible Pharmacological Approach Targeting Endoplasmic Reticulum Stress to Ameliorate Leptin Resistance in Obesity

    PubMed Central

    Hosoi, Toru; Ozawa, Koichiro

    2016-01-01

    Obesity is associated with metabolic syndrome, such as diabetes, hypertension, and hyperlipidemia. Therefore, drug development for the treatment of obesity is needed. Leptin is an anti-obesity hormone that inhibits food intake and increases energy metabolism, and, as such, treatments involving leptin were expected to be beneficial for obesity; however, since most obese patients are in a state of leptin resistance, these treatments may not be useful. Therefore, the amelioration of leptin resistance has recently been attracting interest as a treatment for obesity. The mechanisms underlying the development of leptin resistance need to be elucidated in more detail. Endoplasmic reticulum (ER) stress was recently suggested to be involved in the pathogenesis of leptin resistance. The molecular mechanisms responsible for leptin resistance and possible pharmacological treatments for obesity have been discussed herein, with a focus on ER stress. PMID:27375555

  4. PET Imaging of Leptin Biodistribution and Metabolism in Rodents and Primates

    PubMed Central

    Ceccarini, Giovanni; Flavell, Robert R; Butelman, Eduardo R; Synan, Michael; Willnow, Thomas E; Bar-Dagan, Maya; Goldsmith, Stanley J; Kreek, Mary J; Kothari, Paresh; Vallabhajosula, Shankar; Muir, Tom W; Friedman, Jeffrey M

    2010-01-01

    Summary Here we report the first PET imaging studies of leptin's systemic biodistribution in vivo. PET imaging using 18F and 68Ga labeled leptin revealed that in mouse the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys 15% of labeled leptin localized to red bone marrow which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showing that leptin modulates immune function. These experiments set the stage for similar studies in humans to assess the extent to which alterations of leptin's biodistribution might contribute to obesity and also provide a novel and general chemical strategy for 18F labeling of proteins for PET imaging of other polypeptide hormones. PMID:19656493

  5. Transplantation of mature adipocyte-derived dedifferentiated fat cells promotes locomotor functional recovery by remyelination and glial scar reduction after spinal cord injury in mice.

    PubMed

    Yamada, Hiromi; Ito, Daisuke; Oki, Yoshinao; Kitagawa, Masato; Matsumoto, Taro; Watari, Tosihiro; Kano, Koichiro

    2014-11-14

    Mature adipocyte-derived dedifferentiated fat cells (DFAT) have a potential to be useful as new cell-source for cell-based therapy for spinal cord injury (SCI), but the mechanisms remain unclear. The objective of this study was to examine whether DFAT-induced functional recovery is achieved through remyelination and/or glial scar reduction in a mice model of SCI. To accomplish this we subjected adult female mice (n=22) to SCI. On the 8th day post-injury locomotor tests were performed, and the mice were randomly divided into two groups (control and DFAT). The DFAT group received stereotaxic injection of DFAT, while the controls received DMEM medium. Functional tests were conducted at repeated intervals, until the 36th day, and immunohistochemistry or staining was performed on the spinal cord sections. DFAT transplantation significantly improved locomotor function of their hindlimbs, and promoted remyelination and glial scar reduction, when compared to the controls. There were significant and positive correlations between promotion of remyelination or/and reduction of glial scar, and recovery of locomotor function. Furthermore, transplanted DFAT expressed markers for neuron, astrocyte, and oligodendrocyte, along with neurotrophic factors, within the injured spinal cord. In conclusion, DFAT-induced functional recovery in mice after SCI is probably mediated by both cell-autonomous and cell-non-autonomous effects on remyelination of the injured spinal cord. PMID:25451251

  6. Leptin in early life: a key factor for the development of the adult metabolic profile.

    PubMed

    Granado, Miriam; Fuente-Martín, Esther; García-Cáceres, Cristina; Argente, Jesús; Chowen, Julie A

    2012-01-01

    Leptin levels during the perinatal period are important for the development of metabolic systems involved in energy homeostasis. In rodents, there is a postnatal leptin surge, with circulating leptin levels increasing around postnatal day (PND) 5 and peaking between PND 9 and PND 10. At this time circulating leptin acts as an important trophic factor for the development of hypothalamic circuits that control energy homeostasis and food seeking and reward behaviors. Blunting the postnatal leptin surge results in long-term leptin insensitivity and increased susceptibility to diet-induced obesity during adulthood. Pharmacologically increased leptin levels in the postnatal period also have long-term effects on metabolism. Nevertheless, this effect is controversial as postnatal hyperleptinemia is reported to both increase and decrease the predisposition to obesity in adulthood. The different effects reported in the literature could be explained by the different moments at which this hormone was administered, suggesting that modifications of the neonatal leptin surge at specific time points could selectively affect the development of central and peripheral systems that are undergoing modifications at this moment resulting in different metabolic and behavioral outcomes. In addition, maternal nutrition and the hormonal environment during pregnancy and lactation may also modulate the offspring's response to postnatal modifications in leptin levels. This review highlights the importance of leptin levels during the perinatal period in the development of metabolic systems that control energy homeostasis and how modifications of these levels may induce long-lasting and potentially irreversible effects on metabolism.

  7. Exercise-Associated Amenorrhea: Are Altered Leptin Levels an Early Warning Sign?

    ERIC Educational Resources Information Center

    Warren, Michelle P.; Ramos, Russalind H.; Bronson, Emily M.

    2002-01-01

    Although the exact cause of the female athlete triad (amenorrhea, disordered eating, and osteoporosis) is unknown, recent research implicates leptin, a hormone secreted by adipocytes. Leptin may be an important indicator of nutritional status and may play a role in reproductive function. Physicians who develop a plan for early recognition and…

  8. Leptin as a Marker of Body Fat and Hyperinsulinemia in College Students

    ERIC Educational Resources Information Center

    Kempf, Angela M.; Strother, Myra L.; Li, Chaoyang; Kaur, Harsohena; Huang, Terry T-K.

    2006-01-01

    Little is known about obesity and insulin resistance in college students. Leptin is a hormone secreted by fat cells and has been shown to strongly correlate with both obesity and insulin resistance in children and adults. We investigated associations of leptin with insulin secretion and action in 119 normal-weight students aged 18-24 years. Leptin…

  9. Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes

    PubMed Central

    German, Jonathan P.; Wisse, Brent E.; Thaler, Joshua P.; Oh-I, Shinsuke; Sarruf, David A.; Ogimoto, Kayoko; Kaiyala, Karl J.; Fischer, Jonathan D.; Matsen, Miles E.; Taborsky, Gerald J.; Schwartz, Michael W.; Morton, Gregory J.

    2010-01-01

    OBJECTIVE Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS Adult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine

  10. Immunohistochemical Expression of Leptin in Non Melanoma Skin Cancer

    PubMed Central

    Farag, Azza G.A.; El-Dien, Marwa Mohammed Serag

    2016-01-01

    Introduction Obesity in adults is associated with numerous health disorders including some forms of cancer. Various epidemiological studies have found a link between excess adiposity and malignant melanoma; however, the association with non melanoma skin cancer is questionable. Leptin is a hormone produced mainly by the adipose tissue and its serum level may reflect body mass index. Leptin is reported to promote proliferation and angiogenesis and deregulate apoptosis, therefore facilitates the process of carcinogenesis. Aim The current study tried to assess leptin localization and expression in non melanoma skin cancer to verify its possible role in pathogenesis of this cancer. Materials and Methods This study was carried out on 13 Basal Cell Carcinoma (BCC) cases and 14 Squamous Cell Carcinoma (SCC) cases together with 19 normal skin biopsies as a control group using immunohistochemical method. Results Leptin was expressed in 52.6% of the normal epidermis with pure cytoplasmic and both cytoplasmic and nuclear staining patterns. All cases of SCC (100%) and two cases of BCC (15.4%) showed leptin expression in tumour cells whereas nuclear expression was in favour of SCC. Stromal expression of leptin was seen in both SCC (57.1%) and BCC (38.5%) without significant differences. Percentage of leptin expression by tumour cells in SCC showed positive linear correlation with tumour size (p=0.02) and microvessel density (p=0.000). Stromal expression of leptin in SCC was associated with large tumour size (p=0.04), advanced stage (p=0.01) and tumours arising in sites other than head and neck (p=0.01). Conclusion Leptin could have a more important role in pathogenesis of cutaneous SCC rather than BCC that may reflect the trivial role of obesity in induction of BCC. The expression of leptin by tumour and stromal cells of SCC could co-operate in its progression by promoting angiogenesis with subsequently acquiring large tumour size and then advanced stage. PMID:27656540

  11. Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice.

    PubMed

    Motyl, Katherine J; McCabe, Laura R

    2009-02-01

    Leptin is a hormone secreted by adipocytes that is implicated in the regulation of bone density. Serum leptin levels are decreased in rodent models of type 1 (T1-) diabetes and in diabetic patients. Whether leptin mediates diabetic bone changes is unclear. Therefore, we treated control and T1-diabetic mice with chronic (28 days) subcutaneous infusion of leptin or saline to elucidate the therapeutic potential of leptin for diabetic osteoporosis. Leptin prevented the increase of marrow adipocytes and the increased aP2 expression that we observed in vehicle-treated diabetic mice. However, leptin did not prevent T1-diabetic decreases in trabecular bone volume fraction or bone mineral density in tibia or vertebrae. Consistent with this finding, markers of bone formation (osteocalcin RNA and serum levels) in diabetic mice were not restored to normal levels with leptin treatment. Interestingly, markers of bone resorption (TRAP5 RNA and serum levels) were decreased in diabetic mice by leptin treatment. In summary, we have demonstrated a link between low leptin levels in T1-diabetes and marrow adiposity. However, leptin treatment alone was not successful in preventing bone loss.

  12. Role of leptin in female reproduction.

    PubMed

    Pérez-Pérez, Antonio; Sánchez-Jiménez, Flora; Maymó, Julieta; Dueñas, José L; Varone, Cecilia; Sánchez-Margalet, Víctor

    2015-01-01

    Reproductive function is dependent on energy resources. The role of weight, body composition, fat distribution and the effect of diet have been largely investigated in experimental female animals as well as in women. Any alteration in diet and/or weight may induce abnormalities in timing of sexual maturation and fertility. However, the cellular mechanisms involved in the fine coordination of energy balance and reproduction are largely unknown. The brain and hypothalamic structures receive endocrine and/or metabolic signals providing information on the nutritional status and the degree of fat stores. Adipose tissue acts both as a store of energy and as an active endocrine organ, secreting a large number of biologically important molecules termed adipokines. Adipokines have been shown to be involved in regulation of the reproductive functions. The first adipokine described was leptin. Extensive research over the last 10 years has shown that leptin is not only an adipose tissue-derived messenger of the amount of energy stores to the brain, but also a crucial hormone/cytokine for a number of diverse physiological processes, such as inflammation, angiogenesis, hematopoiesis, immune function, and most importantly, reproduction. Leptin plays an integral role in the normal physiology of the reproductive system with complex interactions at all levels of the hypothalamic-pituitary gonadal (HPG) axis. In addition, leptin is also produced by placenta, where it plays an important autocrine function. Observational studies have demonstrated that states of leptin excess, deficiency, or resistance can be associated with abnormal reproductive function. This review focuses on the leptin action in female reproduction.

  13. Leptin into the rostral ventral lateral medulla (RVLM) augments renal sympathetic nerve activity and blood pressure

    PubMed Central

    Barnes, Maria J.; McDougal, David H.

    2014-01-01

    Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activity. Therefore, leptin is emerging as a major contributor to the hypertensive state observed in obesity. Sympathetic control of blood pressure is maintained principally by autonomic reflex control circuits in the caudal brainstem. The rostral ventral-lateral medulla (RVLM) is the primary regulator of the sympathetic nervous system, sending excitatory fibers to sympathetic preganglionic neurons to regulate sympathetic control over resistance vessels and blood pressure. Previous studies from our laboratory have shown that neurons in the ventral lateral medulla express leptin receptors (ObRb). Our present study using pseudo-rabies multi-synaptic retrograde tract tracing and immunohistochemical methods revealed that neurons within the RVLM that send sympathetic projections to the kidney express leptin receptors. Acute microinjection of leptin (1 and 3 μg; 40 nL) into the RVLM evoked a significant increase in Mean Arterial Pressure (MAP) and renal sympathetic nerve activity (RSNA). When the 3 μg dose of leptin was preceded with a leptin antagonist, (SLAN-4; 1 ng), it attenuated the cardiovascular response of leptin. Taken together, these data suggest that leptin's actions within the RVLM may influence blood pressure and renal sympathetic nerve activity. PMID:25152707

  14. Leptin secretion and leptin receptor in the human stomach

    PubMed Central

    Sobhani, I; Bado, A; Vissuzaine, C; Buyse, M; Kermorgant, S; Laigneau, J; Attoub, S; Lehy, T; Henin, D; Mignon, M; Lewin, M

    2000-01-01

    BACKGROUND AND AIM—The circulating peptide leptin produced by fat cells acts on central receptors to control food intake and body weight homeostasis. Contrary to initial reports, leptin expression has also been detected in the human placenta, muscles, and recently, in rat gastric chief cells. Here we investigate the possible presence of leptin and leptin receptor in the human stomach.
METHODS—Leptin and leptin receptor expression were assessed by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot analysis on biopsy samples from 24 normal individuals. Fourteen (10 healthy volunteers and four patients with non-ulcer dyspepsia and normal gastric mucosa histology) were analysed for gastric secretions. Plasma and fundic mucosa leptin content was determined by radioimmunoassay.
RESULTS—In fundic biopsies from normal individuals, immunoreactive leptin cells were found in the lower half of the fundic glands. mRNA encoding ob protein was detected in the corpus of the human stomach. The amount of fundic leptin was 10.4 (3.7) ng leptin/g mucosa, as determined by radioimmunoassay. Intravenous infusions of pentagastrin or secretin caused an increase in circulating leptin levels and leptin release into the gastric juice. The leptin receptor was present in the basolateral membranes of fundic and antral gastric cells. mRNA encoding Ob-RL was detected in both the corpus and antrum, consistent with a protein of ~120 kDa detected by immunoblotting.
CONCLUSION—These data provide the first evidence of the presence of leptin and leptin receptor proteins in the human stomach and suggest that gastric epithelial cells may be direct targets for leptin. Therefore, we conclude that leptin may have a physiological role in the human stomach, although much work is required to establish this.


Keywords: leptin; leptin receptor; human stomach; gastrin; secretin PMID:10896907

  15. Two isoforms of leptin in the White-clouds Mountain minnow (Tanichthys albonubes): Differential regulation by estrogen despite similar response to fasting.

    PubMed

    Chen, Ting; Chen, Shuang; Ren, Chunhua; Hu, Chaoqun; Tang, Dongsheng; Yan, Aifen

    2016-01-01

    Leptin has been well-established as a canonical anorexic peptide hormone in mammals, though much of its function in fish remains obscure. In this study, the cDNAs of two leptin isoforms (leptin-A and leptin-B) were cloned from the liver of a small cyprinid fish, Tanichthys albonubes. The two T. albonubes leptins, sharing low primary amino acid sequence homology with their mammalian counterparts, and between themselves, are highly conserved in three-dimensional protein structures and gene structures. Liver is a major source of leptin mRNA in T. albonubes with leptin-A being the dominant form. The expression of hepatic leptin-A but not leptin-B mRNA in female fish is significantly higher than in male fish. Transcriptional hepatic levels of leptin-A and leptin-B in both male and female fish were demonstrated to increase after long-term fasting (10-25days) but decline upon re-feeding (3days). Strikingly, estrogen (E2) administration induced only leptin-A but not leptin-B hepatic mRNA expression in both male and female fish. Our study here provides the first evidence for differential regulation of two leptins in fish, and sheds new light on the possible origin of leptin in lower vertebrates.

  16. Human breast milk and adipokines--A potential role for the soluble leptin receptor (sOb-R) in the regulation of infant energy intake and development.

    PubMed

    Zepf, F D; Rao, P; Moore, J; Stewart, R; Ladino, Yuli Martinez; Hartmann, B T

    2016-01-01

    Concentrations of different adipokines in human breast milk are thought to be able to affect energy intake of the infant. Leptin is a hormone synthesized by adipose tissue and the human placenta and favors satiety. The availability of leptin in breast milk is influenced by epithelial cells of the mammary gland that are known to be able to produce leptin, as well as leptin from maternal circulation that is transported to the breast milk, and which can thus in turn reach neonatal blood after absorption. Research so far as mainly focused on leptin concentrations in breast milk. However, evidence suggests that in addition to leptin concentrations levels of the so-called soluble leptin receptor (sOb-R), the main high-affinity binding protein for leptin in humans, are necessary in order to calculate the free leptin index (FLI) and to assess function of the leptin axis. FLI is calculated from the ratio of leptin to the sOb-R, and serves as the main parameter for assessing function of the leptin axis throughout maturation and development. Here we propose that assessing sOb-R levels in addition to leptin concentrations in breast milk could serve as a valuable tool to investigate effects of the leptin axis in breast milk because sOb-R concentrations can impact available leptin levels, and which in turn can have significant implications for infant energy intake and related development.

  17. Analysis of leptin signalling in hematopoietic cells using an adapted MAPPIT strategy.

    PubMed

    Montoye, T; Piessevaux, J; Lavens, D; Wauman, J; Catteeuw, D; Vandekerckhove, J; Lemmens, I; Tavernier, J

    2006-05-29

    The adipocyte-secreted hormone leptin participates in the regulation of hematopoiesis and enhances proliferation of hematopoietic cells. We used an adaptation of the MAPPIT mammalian two-hybrid method to study leptin signalling in a hematopoietic setting. We confirmed the known interactions of suppressor of cytokine signalling 3 (SOCS3) and STAT5 with the Y985 and Y1077 motifs of the leptin receptor, respectively. We also provide evidence for novel interactions at the Y1077 motif, including phospholipase C gamma and several members of the SOCS protein family, further underscoring the important role of the Y1077 motif in leptin signalling. PMID:16698021

  18. Secretome-derived isotope tags (SDIT) reveal adipocyte-derived apolipoprotein C-I as a predictive marker for cardiovascular disease.

    PubMed

    Li, Rong-Xia; Ding, Yu-Bo; Zhao, Shi-Lin; Xiao, Yuan-Yuan; Li, Qing-run; Xia, Fang-Ying; Sun, Liang; Lin, Xu; Wu, Jia-Rui; Liao, Kan; Zeng, Rong

    2012-05-01

    We developed a quantitative strategy, named secretome-derived isotopic tag (SDIT), to concurrently identify and quantify the adipocyte-secreted plasma proteins from normal and high-fat-diet (HFD) induced obese mice, based on the application of isotope-labeled secreted proteins from cultured mouse adipocytes as internal standards. We detected 197 proteins with significant changes between normal and obese mice plasma. Importantly, a novel adipocyte-secreted plasma protein, apolipoprotein C-I (apoC-I), significantly increased in the obese mice plasma. The expression and secretion of adipocyte apoC-I was detected in differentiated 3T3-L1 and primary rat adipocytes. Our in vitro experiments proved that functional Golgi apparatus was required for apoC-I secretion. Additionally, obese mice had increased apoC-I production in adipose tissue. Population survey of 367 participants showed that the plasma level of apoC-I was significantly increased in obese individuals compared with healthy individuals. After multiple adjustments for age and sex, the odds ratios for risk factors of cardiovascular disease including high LDL cholesterol, hypercholesterolemia, and hypertriglyceridemia, respectively, were used to compare the highest with the lowest apoC-I quartile. Taken together, our studies provide a novel strategy to concurrently identify and quantify tissue-specific secreted proteins. This strategy can be used to identify the largest global characterization of adipocyte-derived plasma proteome and provides a potential disease-related biomarker for clinical diagnoses. By selectively analyzing adipocyte-secreted proteins in plasma from obese vs lean murine and/or human subjects, we discovered that apoC-I is an adipocyte-secreted plasma protein and a predictive marker for cardiovascular disease.

  19. Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERα pathway

    SciTech Connect

    Khanal, Tilak; Kim, Hyung Gyun; Do, Minh Truong; Choi, Jae Ho; Won, Seong Su; Kang, Wonku; Chung, Young Chul; Jeong, Tae Cheon; Jeong, Hye Gwang

    2014-05-15

    Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells. - Highlights: • Leptin increased 4-hydroxyoestradiol in MCF-7 breast cancer cells. • Leptin activated ERK and Akt kinases related to ERα phosphorylation. • Leptin induces phosphorylation of ERα at serine residues 118 and 167. • Leptin induces ERE-luciferase activity.

  20. Leptin, GH, PRL, insulin and metabolic parameters throughout the dry period and lactation in dairy cows.

    PubMed

    Accorsi, P A; Govoni, N; Gaiani, R; Pezzi, C; Seren, E; Tamanini, C

    2005-06-01

    Leptin may play a role in the endocrine-metabolic processes that guarantee the physiological course of lactation in dairy cattle. This study was aimed at determining the changes in plasma concentrations of leptin and some of the main hormones and metabolites involved in the lactogenetic process in high-yielding dairy cows throughout lactation; we also wanted to assess whether leptin secretion is subjected to seasonal influences. Blood samples were collected from 23 Italian Friesian dairy cows from the end of a lactation to the ninth month of the subsequent one; in addition, blood was sampled from 47 dairy cows in different phases of lactation during February and July. Plasma concentrations of leptin, growth hormone (GH), insulin, prolactin (PRL), glucose, non-esterified fatty acids (NEFA) and urea were quantified by either validated radioimmunoassay (RIA) or enzymatic colorimetric methods. At the beginning of lactation, GH concentrations significantly increased, while a significant reduction occurred in leptin and insulin. This endocrine condition, such as the significant increase in NEFA plasma concentrations, is indicative of a marked lipid mobilization. In the more advanced stages of lactation, when both energy and protein balances become positive, leptin plasma concentrations increased, whereas GH and NEFA concentrations declined. During the summer months, a significant increase in leptin plasma concentrations, irrespective of the phase of lactation, was observed. Collectively, our findings suggest that, in dairy cows, leptin may represent a 'metabolic signal' of animal's status of fattening and nutritional level; in addition, leptin seems to be influenced by photoperiod and environmental temperature.

  1. Localization and role of leptin in the thyroid gland of the lizard Podarcis sicula (Reptilia, Lacertidae).

    PubMed

    Sciarrillo, Rosaria; Virgilio, Francesca; De Falco, Maria; Laforgia, Vincenza; Varano, Lorenzo; Paolucci, Marina

    2005-08-01

    Leptin, the product of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. The hypothalamus-pituitary-thyroid axis is markedly influenced by the metabolism status, being suppressed during food deprivation. The present study was designed to ascertain whether (1) lizard thyroid gland expresses the long form of leptin receptor (Ob-Rb) and (2) the leptin administration affects the thyroid gland activity in this species (and to verify whether leptin plays a similar role in reptiles as observed in the other vertebrates). The presence of leptin receptor in the thyroid gland of Podarcis sicula was demonstrated by immunohistochemical technique (avidin-biotin-peroxidase complex--ABC method). The role of leptin in the control of thyroid gland activity was studied in vivo using light microscopy (LM) technique coupled to a specific radioimmunoassay for thyroid-stimulating hormone (TSH) and thyroid hormones (T4 and T3). Leptin (0.1 mg/100 g body wt)/day increased T4 and T3 release for 3 days but decreased the plasma concentration of TSH; using LM clear signs of stimulation in the thyroid gland were observed. These findings suggest that systemic administration of leptin stimulates the morphophysiology of the thyroid gland in the lizard through a direct mechanism involving Ob-Rb.

  2. Effects of leptin and leptin receptor gene polymorphisms on lung cancer.

    PubMed

    Unsal, Meftun; Kara, Nurten; Karakus, Nevin; Tural, Sengul; Elbistan, Mehmet

    2014-10-01

    Leptin (LEP), an adipocyte-derived cytokine, has been reported to participate in carcinogenesis. Elevated levels of systemic and pulmonary LEP are associated with diseases related to lung injury and lung cancer. The purpose of the present study was to investigate if the LEP and leptin receptor (LEPR) gene polymorphisms are associated with lung cancer in a cohort of Turkish population. One hundred and sixty-two lung cancer patients and 130 healthy controls were included in the study. The genotypes of LEP gene -2548G > A and LEPR gene Q223R polymorphisms were determined using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) analysis. The genotype frequencies of LEP -2548G > A polymorphism showed statistically significant differences between lung cancer patients and controls (p = 0.007). GA + AA genotypes and A allele of LEP -2548G > A polymorphism was found to be susceptibility factors for lung cancer (p = 0.003, odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.32-4.10; p = 0.003, OR 1.65, 95 % CI 1.18-2.29, respectively). The genotype and allele frequencies of LEPR Q223R polymorphism did not show any statistically significant differences between lung cancer patients and controls (p = 0.782 and p = 0.762, respectively). Although AA-QQ and AA-QR combined genotypes of LEP -2548G > A-LEPR Q223R loci were significantly higher in lung cancer patients (p = 0.020 and p = 0.047, respectively), GG-QQ, GG-QR, and AA-RR combined genotypes were significantly higher in control group. As a result, susceptibility effects of LEP -2548G > A polymorphism alone or in combination with LEPR Q223R polymorphism on lung cancer were observed. Further studies are necessary to prove the association of LEP and LEPR gene polymorphisms with lung cancer.

  3. Leptin signaling in GFAP-expressing adult glia cells regulates hypothalamic neuronal circuits and feeding

    PubMed Central

    Kim1, Jae Geun; Suyama, Shigetomo; Koch, Marco; Jin, Sungho; Argente-Arizon, Pilar; Argente, Jesus; Liu, Zhong-Wu; Zimmer, Marcelo R.; Jeong, Jin Kwon; Szigeti-Buck, Klara; Gao, Yuanqing; Garcia-Caceres, Cristina; Yi, Chun-Xia; Salmaso, Natalina; Vaccarino, Flora M.; Chowen, Julie; Diano, Sabrina; Dietrich, Marcelo O; Tschöp, Matthias H.; Horvath, Tamas L.

    2014-01-01

    We have shown that synaptic re-organization of hypothalamic feeding circuits in response to metabolic shifts involves astrocytes, cells that can directly respond to the metabolic hormone, leptin, in vitro. It is not known whether the role of glia cells in hypothalamic synaptic adaptions is active or passive. Here we show that leptin receptors are expressed in hypothalamic astrocytes and that conditional, adult deletion of leptin receptors in astrocytes leads to altered glial morphology, decreased glial coverage and elevated synaptic inputs onto pro-opiomelanocortin (POMC)- and Agouti-related protein (AgRP)-producing neurons. Leptin-induced suppression of feeding was diminished, while rebound feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data unmask an active role of glial cells in the initiation of hypothalamic synaptic plasticity and neuroendocrine control of feeding by leptin. PMID:24880214

  4. Relationship between Plasma Leptin Level and Chronic Kidney Disease

    PubMed Central

    Shankar, Anoop; Syamala, Shirmila; Xiao, Jie; Muntner, Paul

    2012-01-01

    Background. Leptin is an adipose tissue-derived hormone shown to be related to several metabolic, inflammatory, and hemostatic factors related to chronic kidney disease. Recent animal studies have reported that infusion of recombinant leptin into normal rats for 3 weeks fosters the development of glomerulosclerosis. However, few studies have examined the association between leptin and CKD in humans. Therefore, we examined the association between plasma leptin levels and CKD in a representative sample of US adults. Methods. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n = 5820, 53.6% women). Plasma leptin levels were categorized into quartiles (≤4.3 Fg/L, 4.4–8.7 Fg/L, 8.8–16.9 Fg/L, >16.9 Fg/L). CKD was defined as a glomerular filtration rate of <60 mL/min/1.73 m2 estimated from serum creatinine. Results. Higher plasma leptin levels were associated with CKD after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index (BMI), diabetes, hypertension, and serum cholesterol. Compared to quartile 1 of leptin (referent), the odds ratio (95% confidence interval) of CKD associated with quartile 4 was 3.31 (1.41 to 7.78); P-trend = 0.0135. Subgroup analyses examining the relation between leptin and CKD by gender, BMI categories, diabetes, and hypertension status also showed a consistent positive association. Conclusion. Higher plasma leptin levels are associated with CKD in a representative sample of US adults. PMID:22666590

  5. Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus

    PubMed Central

    Guimond, Damien; Diabira, Diabe; Porcher, Christophe; Bader, Francesca; Ferrand, Nadine; Zhu, Mingyan; Appleyard, Suzanne M.; Wayman, Gary A.; Gaiarsa, Jean-Luc

    2014-01-01

    It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission. PMID:25177272

  6. Positive relationship between plasma leptin level and hypertension.

    PubMed

    Shankar, Anoop; Xiao, Jie

    2010-10-01

    Leptin is an adipose tissue-derived hormone shown to be related to metabolic, inflammatory, and hemostatic factors involved in hypertension development. Animal studies suggest that higher leptin levels may activate the sympathetic nervous system and cause elevations in blood pressure (BP). However, few studies have examined the association between leptin and hypertension in humans. Also it is not clear whether this association is present among women as well as men. Therefore, we examined the association between plasma leptin levels and hypertension in a representative sample of US adults. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n=5599; 54.7% women). Plasma leptin levels were categorized into quartiles (women: <7.68, 7.68 to 13.18, 13.19 to 21.70, >21.70 fg/L; men: <2.64, 2.64 to 4.36, 4.37 to 7.12, >7.12 fg/L). Hypertension was defined as BP-reducing medication use or having systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg. We found that higher plasma leptin levels were positively associated with hypertension after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index, diabetes mellitus, serum cholesterol, and C-reactive protein. Compared with quartile 1 of leptin (referent), the odds ratio (95% CI) of hypertension associated with quartile 4 was 1.89 (1.24 to 2.09; P for trend=0.0036). Subgroup analyses examining the relation between leptin and hypertension by sex and body mass index categories also showed a consistent positive association. In conclusion, higher plasma leptin levels are associated with hypertension both among women as well as men in a representative sample of US adults.

  7. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

    PubMed

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  8. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

    PubMed

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

    2016-02-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  9. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    PubMed Central

    Kilpeläinen, Tuomas O.; Carli, Jayne F. Martin; Skowronski, Alicja A.; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K.; Drong, Alexander W.; Hayes, James E.; Zhao, Jinghua; Pers, Tune H.; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Greco M, Fabiola Del; Pasko, Dorota; Renström, Frida; Willems, Sara M.; Mahajan, Anubha; Rose, Lynda M.; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E.; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S.; Ju Sung, Yun; Ramos, Yolande F.; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M.; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J. N.; Crosslin, David R.; Dale, Caroline E.; Dastani, Zari; Day, Felix R.; Deelen, Joris; Delgado, Graciela E.; Demirkan, Ayse; Finucane, Francis M.; Ford, Ian; Garcia, Melissa E.; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E.; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A.; Hunter, David J.; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S.; Jørgensen, Marit E.; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A.; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P.; Myers, Richard H.; Männistö, Satu; Nalls, Mike A.; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rathmann, Wolfgang; Rice, Treva K.; Brent Richards, J; Ridker, Paul M.; Sattar, Naveed; Savage, David B.; Söderberg, Stefan; Timpson, Nicholas J.; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R.; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I. A.; Sarzynski, Mark A.; Rao, D. C.; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G.; Heliövaara, Markku; Knekt, Paul B.; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K.; Viikari, Jorma S.; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P.; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W.; van Duijn, Cornelia M.; Harris, Tamara B.; Bouchard, Claude; Allison, Matthew A.; Chasman, Daniel I.; Ohlsson, Claes; Lind, Lars; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; Ferrucci, Luigi; Frayling, Timothy M.; Pramstaller, Peter P.; Borecki, Ingrid B.; Waterworth, Dawn M.; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B.; Eline Slagboom, P; Grallert, Harald; Spector, Tim D.; Jukema, J.W.; Klein, Robert J.; Schadt, Erik E; Franks, Paul W.; Lindgren, Cecilia M.; Leibel, Rudolph L.; Loos, Ruth J. F.

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  10. Leptin inhibits food-deprivation-induced increases in food intake and food hoarding.

    PubMed

    Keen-Rhinehart, Erin; Bartness, Timothy J

    2008-12-01

    Food deprivation stimulates foraging and hoarding and to a much lesser extent, food intake in Siberian hamsters. Leptin, the anorexigenic hormone secreted primarily from adipocytes, may act in the periphery, the brain, or both to inhibit these ingestive behaviors. Therefore, we tested whether leptin given either intracerebroventricularly or intraperitoneally, would block food deprivation-induced increases in food hoarding, foraging, and intake in animals with differing foraging requirements. Hamsters were trained in a running wheel-based food delivery foraging system coupled with simulated burrow housing. We determined the effects of food deprivation and several peripheral doses of leptin on plasma leptin concentrations. Hamsters were then food deprived for 48 h and given leptin (0, 10, 40, or 80 microg ip), and additional hamsters were food deprived for 48 h and given leptin (0, 1.25, 2.5, or 5.0 microg icv). Foraging, food intake, and hoarding were measured postinjection. Food deprivation stimulated food hoarding to a greater degree and duration than food intake. In animals with a foraging requirement, intracerebroventricular leptin almost completely blocked food deprivation-induced increased food hoarding and intake, but increased foraging. Peripheral leptin treatment was most effective in a sedentary control group, completely inhibiting food deprivation-induced increased food hoarding and intake at the two highest doses, and did not affect foraging at any dose. Thus, the ability of leptin to inhibit food deprivation-induced increases in ingestive behaviors differs based on foraging effort (energy expenditure) and the route of administration of leptin administration.

  11. Differential Acute and Chronic Effects of Leptin on Hypothalamic Astrocyte Morphology and Synaptic Protein Levels

    PubMed Central

    García-Cáceres, Cristina; Fuente-Martín, Esther; Burgos-Ramos, Emma; Granado, Miriam; Frago, Laura M.; Barrios, Vicente; Horvath, Tamas

    2011-01-01

    Astrocytes participate in neuroendocrine functions partially through modulation of synaptic input density in the hypothalamus. Indeed, glial ensheathing of neurons is modified by specific hormones, thus determining the availability of neuronal membrane space for synaptic inputs, with the loss of this plasticity possibly being involved in pathological processes. Leptin modulates synaptic inputs in the hypothalamus, but whether astrocytes participate in this action is unknown. Here we report that astrocyte structural proteins, such as glial fibrillary acidic protein (GFAP) and vimentin, are induced and astrocyte morphology modified by chronic leptin administration (intracerebroventricular, 2 wk), with these changes being inversely related to modifications in synaptic protein densities. Similar changes in glial structural proteins were observed in adult male rats that had increased body weight and circulating leptin levels due to neonatal overnutrition (overnutrition: four pups/litter vs. control: 12 pups/litter). However, acute leptin treatment reduced hypothalamic GFAP levels and induced synaptic protein levels 1 h after administration, with no effect on vimentin. In primary hypothalamic astrocyte cultures leptin also reduced GFAP levels at 1 h, with an induction at 24 h, indicating a possible direct effect of leptin. Hence, one mechanism by which leptin may affect metabolism is by modifying hypothalamic astrocyte morphology, which in turn could alter synaptic inputs to hypothalamic neurons. Furthermore, the responses to acute and chronic leptin exposure are inverse, raising the possibility that increased glial activation in response to chronic leptin exposure could be involved in central leptin resistance. PMID:21343257

  12. In vivo but not in vitro leptin enhances lymphocyte proliferation in Siberian hamsters (Phodopus sungorus).

    PubMed

    Demas, Gregory E

    2010-04-01

    Mounting an immune response requires a relatively substantial investment of energy and marked reductions in energy availability can suppress immune function and presumably increase disease susceptibility. We have previously demonstrated that a moderate reduction in energy stores by partial surgical lipectomy impairs humoral immunity of Siberian hamsters (Phodopus sungorus) and is mediated, in part, by changes in the adipose tissue hormone leptin. The goals of the present study were to assess the role of leptin in cell-mediated immunity and to determine if the potential effects of leptin on immunity are via the direct actions of this hormone on lymphocytes, or indirect, via the sympathetic nervous system (SNS). In Experiment 1, hamsters received osmotic minipumps containing either murine leptin (0.5 microl/h) or vehicle alone for 10 days and splenocyte proliferation in response to the T-cell mitogen Concanavalin A (Con A) was determined. In Experiment 2, Con A-induced splenocyte proliferation was tested in the presence or absence of leptin in vitro. In Experiment 3, exogenous leptin was administered to intact or sympathetically denervated hamsters. Hamsters treated with in vivo leptin displayed increased splenocyte proliferation compared with control hamsters receiving vehicle. In contrast, in vitro leptin had no effect on splenocyte proliferation. Sympathetic denervation attenuated, but did not block, leptin-induced increases in immunity. Taken together, these results are consistent with the idea that leptin can enhance cell-mediated immunity; the SNS appears to contribute, least in part, to leptin-induced increases in immunity. Importantly, these findings confirm previous studies that leptin serves as an important endocrine link between energy balance and immunity.

  13. The leptin system and its expression at different nutritional and pregnant stages in lined seahorse (Hippocampus erectus)

    PubMed Central

    Zhang, Huixian; Qin, Geng; Zhang, Yanhong; Li, Shuisheng

    2016-01-01

    ABSTRACT Leptin is an essential hormone for the regulation of energy metabolism and food intake in vertebrate animals. To better understand the physiological roles of leptin in nutrient regulation in paternal ovoviviparous fish (family Syngnathidae), the present study cloned the full-length of leptin-a and leptin receptor (lepr) genes in lined seahorse (Hippocampus erectus). Results showed that there was a 576-bp intron between two exons in leptin-a gene but no leptin-b gene in seahorse. Although the primary amino acid sequence conservation of seahorse leptin-a was very low, the 3-D structure modeling of seahorse leptin-a revealed strong conservation of tertiary structure with other vertebrates. Seahorse leptin-a mRNA was highly expressed in brain, whereas lepr mRNA was mainly expressed in ovary and gill. Interestingly, both leptin-a and lepr mRNA were expressed in the brood pouch of male seahorse, suggesting the leptin system plays a role during the male pregnancy. Physiological experiments showed that the expression of hepatic leptin-a and lepr mRNA in unfed seahorses was significantly higher than that in those fed 100%, as well as 60%, of their food during the fasting stage, showing that seahorse might initiate the leptin system to regulate its energy metabolism while starving. Moreover, the expression of leptin-a in the brood pouch of pregnant seahorse was significantly upregulated compared with non-pregnant seahorse, whereas the expression of lepr was downregulated, suggesting that the leptin system might be involved in the male pregnancy. In conclusion, the leptin system plays a role in the energy metabolism and food intake, and might provide new insights into molecular regulation of male pregnancy in seahorse. PMID:27628034

  14. Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen.

    PubMed

    Shi, Zhigang; Brooks, Virginia L

    2015-04-01

    Obesity and hypertension are commonly associated, and activation of the sympathetic nervous system is considered to be a major contributor, at least in part due to the central actions of leptin. However, while leptin increases sympathetic nerve activity (SNA) in males, whether leptin is equally effective in females is unknown. Here, we show that intracerebroventricular (i.c.v.) leptin increases lumbar (LSNA) and renal (RSNA) SNA and baroreflex control of LSNA and RSNA in α-chloralose anaesthetized female rats, but only during pro-oestrus. In contrast, i.c.v. leptin increased basal and baroreflex control of splanchnic SNA (SSNA) and heart rate (HR) in rats in both the pro-oestrus and dioestrus states. The effects of leptin on basal LSNA, RSNA, SSNA and HR were similar in males and pro-oestrus females; however, i.c.v. leptin increased mean arterial pressure (MAP) only in males. Leptin did not alter LSNA or HR in ovariectomized rats, but its effects were normalized with 4 days of oestrogen treatment. Bilateral nanoinjection of SHU9119 into the paraventricular nucleus of the hypothalamus (PVN), to block α-melanocyte-stimulating hormone (α-MSH) type 3 and 4 receptors, decreased LSNA in leptin-treated pro-oestrus but not dioestrus rats. Unlike leptin, i.c.v. insulin infusion increased basal and baroreflex control of LSNA and HR similarly in pro-oestrus and dioestrus rats; these responses did not differ from those in male rats. We conclude that, in female rats, leptin's stimulatory effects on SNA are differentially enhanced by oestrogen, at least in part via an increase in α-MSH activity in the PVN. These data further suggest that the actions of leptin and insulin to increase the activity of various sympathetic nerves occur via different neuronal pathways or cellular mechanisms. These results may explain the poor correlation in females of SNA with adiposity, or of MAP with leptin. PMID:25398524

  15. Leptin and mTOR: partners in metabolism and inflammation.

    PubMed

    Maya-Monteiro, Clarissa M; Bozza, Patricia T

    2008-06-15

    Leptin is both a hormone/cytokine that plays a major role in the regulation of feeding and energy expenditure. Beyond its central role in the hypothalamus, leptin modulates peripheral tissues' responses to growth and storage based on nutrient availability, and it regulates the innate and adaptive immune responses. mTOR (mammalian Target of Rapamycin) is a core component of intracellular signaling for cellular growth, mRNA translation, and metabolism. Here, we review recent findings on the cross talk between mTOR and leptin signaling. Important roles for mTOR on leptin signaling have been established both in hypothalamic centers to control food intake and in peripheral cells to regulate lipid metabolism and inflammation. Leptin directly activates resident macrophages to form ADRP-enriched lipid droplets and enhances eicosanoid production via a mechanism that is dependent on activation of the PI3K/mTOR pathway. Leptin-induced mTOR activation may have implications for obesity-related pathophysiological conditions such as diabetes, cardiovascular disease and cancer. PMID:18583936

  16. Caffeine attenuated ER stress-induced leptin resistance in neurons.

    PubMed

    Hosoi, Toru; Toyoda, Keisuke; Nakatsu, Kanako; Ozawa, Koichiro

    2014-05-21

    Exposing the endoplasmic reticulum (ER) to stress causes the accumulation of unfolded proteins, and subsequently results in ER stress. ER stress may be involved in various disorders such as obesity, diabetes, and neurodegenerative diseases. Leptin is an important circulating hormone, that inhibits food intake and accelerates energy consumption, which suppresses body weight gain. Recent studies demonstrated that leptin resistance is one of the main factors involved in the development of obesity. We and other groups recently reported the role of ER stress in the development of leptin resistance. Therefore, identifying drugs that target ER stress may be a promising fundamental strategy for the treatment of obesity. In the present study, we investigated whether caffeine could affect ER stress and the subsequent development of leptin resistance. We showed that caffeine exhibited chaperone activity, which attenuated protein aggregation. Caffeine also inhibited the ER stress-induced activation of IRE1 and PERK, which suggested the attenuation of ER stress. Moreover, caffeine markedly improved ER stress-induced impairments in the leptin-induced phosphorylation of STAT3. Therefore, these results suggest caffeine may have pharmacological properties that ameliorate leptin resistance by reducing ER stress. PMID:24699176

  17. Role of leptin and leptin receptors in hematological malignancies.

    PubMed

    Uddin, Shahab; Mohammad, Ramzi M

    2016-01-01

    Leptin is an adipose-derived cytokine that has an important role in bodyweight homeostasis and energy balance. There are a number of studies which have suggested that leptin and its receptors dysregulation play a critical role in the development of malignancies including hematological malignancies, mainly via activation of the JAK/STAT pathway which regulates downstream signaling pathways such as PI3K/AKT signaling and ERK1/2. In this review, current understandings of leptin/leptin receptors mediated pathogenesis in various lymphoid malignancies are described. Blocking of the leptin receptor might be a unique therapeutic approach for many hematological malignancies.

  18. Leptin and body mass index in polycystic ovary syndrome

    PubMed Central

    Jalilian, Nasrin; Haghnazari, Lida; Rasolinia, Samira

    2016-01-01

    Objective: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with obesity. Human and animal studies showed a direct relationship between leptin level and obesity, however, results from different studies were mixed. This study investigated the status of leptin level in PCOS and its relationship with body mass index (BMI) in a group of Iranian women with PCOS. Methods: In this cross-sectional study, 40 women with PCOS and 36 healthy women were assigned to experimental and control groups, respectively. Those in the PCOS group were not prescribed any medications for 3 months prior to the study. Fasting blood samples were then collected during the 2nd or 3rd day of menstruation for laboratory measurement of serum total leptin, blood glucose (fasting blood sugar), serum insulin, follicle-stimulating hormone, and luteinizing hormone (LH). Results: Mean BMI of the PCOS and control groups were 26.62 ± 4.03 kg/m2 and 23.52 ± 2.52 kg/m2, respectively (P = 0.006). The mean total leptin in the PCO group was also 10.69 ± 5.37 ng/mL and 5.73 ± 2.36 ng/mL in the control group (P = 0.0001). A significant relationship was found between leptin level and BMI as well as LH level among women with PCOS (P < 0.05). However, there was no significant correlation between leptin and insulin (P > 0.05). Conclusion: The results of this study indicated an increased leptin level among women with PCOS that positively associated with BMI and LH. PMID:27186548

  19. Serum leptin levels during the menstrual cycle of healthy fertile women.

    PubMed

    Quinton, N D; Laird, S M; Okon, M A; Li, T C; Smith, R F; Ross, R J; Blakemore, A I

    1999-01-01

    Leptin is a protein, produced by adipose tissue, which has cytokine and hormonal properties. Serum leptin levels can be considered as a measure of body fat mass, and are involved in regulation of body weight. Previous studies suggest that leptin may have an additional role in reproduction, and there is also evidence for involvement in the hypothalamic-pituitary-gonadal axis. In this study, we investigate the possible changes in serum leptin concentration throughout the menstrual cycle. Samples were collected from apparently healthy, fertile women at different stages in their menstrual cycle, timed precisely according to the luteinising hormone (LH) surge. Mean serum leptin levels were significantly higher in the luteal phase (median 11.4 ng/mL) than in the follicular phase (median 10.0 ng/mL) (P < 0.001). In addition, mean serum leptin levels correlated with body mass index (r = 0.54, P < 0.05), but showed no correlation with luteal-phase progesterone levels. Results showed that levels of serum leptin vary during the menstrual cycle, and add to the mounting evidence that leptin has a role in reproduction. These fluctuations should be taken into account whenever studies are performed using female subjects.

  20. Prolactin affects leptin action in the bovine mammary gland via the mammary fat pad.

    PubMed

    Feuermann, Y; Mabjeesh, S J; Niv-Spector, L; Levin, D; Shamay, A

    2006-11-01

    One of the roles of the endocrine system is to synchronize mammary function. Hormones, such as estrogen, progesterone, and prolactin act directly on the mammary gland. Metabolic hormones, such as GH, glucocorticoids, insulin, and leptin are responsible for coordinating the body's response to metabolic homeostasis. Leptin has been shown to be an important factor in regulating the metabolic adaptation of nutrient partitioning during the energy-consuming processes of lactation. In the present study, we show that leptin is secreted from the mammary fat, and is regulated by prolactin. The expression of alpha-casein in a co-culture of epithelial cells and fat explants was enhanced by prolactin compared with that in epithelial cells cultured alone. Leptin antagonist abolished the effect of leptin on alpha-casein expression in mammary gland explants when exogenous leptin was not present in the medium. This finding supports our hypothesis that the antagonist abolishes the action of endogenous leptin secreted by the mammary adipocytes. These results lead us to the hypothesis that prolactin and leptin act in the bovine mammary gland, via mammary fat pad/adipocytes. PMID:17088410

  1. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.

    PubMed

    Takahashi, N; Waelput, W; Guisez, Y

    1999-01-01

    Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administration of high TNF doses induces acute anorexia, metabolic derangement, inflammation, and eventually shock and death. The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we questioned the role of leptin in TNF-induced pathology. To address this question, we tested mouse strains that were defective either in leptin gene (ob/ob) or in functional leptin receptor gene (db/db), and made use of a receptor antagonist of leptin. Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

  2. Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus.

    PubMed

    Akieda-Asai, Sayaka; Poleni, Paul-Emile; Date, Yukari

    2014-06-01

    CCK and leptin are anorectic hormones produced in the small intestine and white adipose tissue, respectively. Investigating how these hormones act together as an integrated anorectic signal is important for elucidating the mechanisms by which energy balance is maintained. We found here that coadministration of subthreshold CCK and leptin, which individually have no effect on feeding, dramatically reduced food intake in rats. Phosphorylation of AMP-activated protein kinase (AMPK) in the hypothalamus significantly decreased after coinjection of CCK and leptin. In addition, coadministration of these hormones significantly increased mRNA levels of anorectic cocaine- and amphetamine-regulated transcript (CART) and thyrotropin-releasing hormone (TRH) in the hypothalamus. The interactive effect of CCK and leptin on food intake was abolished by intracerebroventricular preadministration of the AMPK activator AICAR or anti-CART/anti-TRH antibodies. These findings indicate that coinjection of CCK and leptin reduces food intake via reduced AMPK phosphorylation and increased CART/TRH in the hypothalamus. Furthermore, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of CCK and leptin to reduce food intake. Food intake reduction induced by coinjection of CCK and leptin was blocked in midbrain-transected rats. Therefore, the neural pathway from hindbrain to hypothalamus plays an important role in transmitting the anorectic signals provided by coinjection of CCK and leptin. Our findings give further insight into the mechanisms of feeding and energy balance.

  3. A sensitive period for environmental regulation of eating behavior and leptin sensitivity.

    PubMed

    Mainardi, Marco; Scabia, Gaia; Vottari, Teresa; Santini, Ferruccio; Pinchera, Aldo; Maffei, Lamberto; Pizzorusso, Tommaso; Maffei, Margherita

    2010-09-21

    Western lifestyle contributes to body weight dysregulation. Leptin down-regulates food intake by modulating the activity of neural circuits in the hypothalamic arcuate nucleus (ARC), and resistance to this hormone constitutes a permissive condition for obesity. Physical exercise modulates leptin sensitivity in diet-induced obese rats. The role of other lifestyle components in modulating leptin sensitivity remains elusive. Environmentally enriched mice were used to explore the effects of lifestyle change on leptin production/action and other metabolic parameters. We analyzed adult mice exposed to environmental enrichment (EE), which showed decreased leptin, reduced adipose mass, and increased food intake. We also analyzed 50-d-old mice exposed to either EE (YEE) or physical exercise (YW) since birth, both of which showed decreased leptin. YEE mice showed no change in food intake, increased response to leptin administration, increased activation of STAT3 in the ARC. The YW leptin-induced food intake response was intermediate between young mice kept in standard conditions and YEE. YEE exhibited increased and decreased ratios of excitatory/inhibitory synapses onto α-melanocyte-stimulating hormone and agouti-related peptide neurons of the ARC, respectively. We also analyzed animals as described for YEE and then placed in standard cages for 1 mo. They showed no altered leptin production/action but demonstrated changes in excitatory/inhibitory synaptic contacts in the ARC similar to YEE. EE and physical activity resulted in improved insulin sensitivity. In conclusion, EE and physical activity had an impact on feeding behavior, leptin production/action, and insulin sensitivity, and EE affected ARC circuitry. The leptin-hypothalamic axis is maximally enhanced if environmental stimulation is applied during development.

  4. Monitoring leptin activity using the chicken leptin receptor.

    PubMed

    Hen, Gideon; Yosefi, Sera; Ronin, Ana; Einat, Paz; Rosenblum, Charles I; Denver, Robert J; Friedman-Einat, Miriam

    2008-05-01

    We report on the construction of a leptin bioassay based on the activation of chicken leptin receptor in cultured cells. A human embryonic kidney (HEK)-293 cell line, stably transfected with the full-length cDNA of chicken leptin receptor together with a STAT3-responsive reporter gene specifically responded to recombinant human and Xenopus leptins. The observed higher sensitivity of chicken leptin receptor to the former is in agreement with the degree of sequence similarity among these species (about 60 and 38% identical amino acids between humans and chickens, and between humans and Xenopus respectively). The specific activation of signal transduction through the chicken leptin receptor, shown here for the first time, suggests that the transition of Gln269 (implicated in the Gln-to-Pro Zucker fatty mutation in rats) to Glu in chickens does not impair its activity. Analysis of leptin-like activity in human serum samples of obese and lean subjects coincided well with leptin levels determined by RIA. Serum samples of pre- and post partum cows showed a tight correlation with the degree of adiposity. However, specific activation of the chicken leptin receptor in this assay was not observed with serum samples from broiler or layer chickens (representing fat and lean phenotypes respectively) or with those from turkey. Similar leptin receptor activation profiles were observed with cells transfected with human leptin receptor. Further work is needed to determine whether the lack of leptin-like activity in the chicken serum samples is due to a lack of leptin in this species or simply to a serum level of leptin that is below the detection threshold.

  5. Monitoring leptin activity using the chicken leptin receptor.

    PubMed

    Hen, Gideon; Yosefi, Sera; Ronin, Ana; Einat, Paz; Rosenblum, Charles I; Denver, Robert J; Friedman-Einat, Miriam

    2008-05-01

    We report on the construction of a leptin bioassay based on the activation of chicken leptin receptor in cultured cells. A human embryonic kidney (HEK)-293 cell line, stably transfected with the full-length cDNA of chicken leptin receptor together with a STAT3-responsive reporter gene specifically responded to recombinant human and Xenopus leptins. The observed higher sensitivity of chicken leptin receptor to the former is in agreement with the degree of sequence similarity among these species (about 60 and 38% identical amino acids between humans and chickens, and between humans and Xenopus respectively). The specific activation of signal transduction through the chicken leptin receptor, shown here for the first time, suggests that the transition of Gln269 (implicated in the Gln-to-Pro Zucker fatty mutation in rats) to Glu in chickens does not impair its activity. Analysis of leptin-like activity in human serum samples of obese and lean subjects coincided well with leptin levels determined by RIA. Serum samples of pre- and post partum cows showed a tight correlation with the degree of adiposity. However, specific activation of the chicken leptin receptor in this assay was not observed with serum samples from broiler or layer chickens (representing fat and lean phenotypes respectively) or with those from turkey. Similar leptin receptor activation profiles were observed with cells transfected with human leptin receptor. Further work is needed to determine whether the lack of leptin-like activity in the chicken serum samples is due to a lack of leptin in this species or simply to a serum level of leptin that is below the detection threshold. PMID:18434362

  6. Phenotypic effects of leptin in an ectotherm: a new tool to study the evolution of life histories and endothermy?

    PubMed

    Niewiarowski, P H; Balk, M L; Londraville, R L

    2000-01-01

    Leptin is a hormone that regulates energy expenditure and body mass in mammals, and it has attracted considerable attention because of its potential in treating human obesity. Comprehensive data from both pathological and non-pathological systems strongly support a role for leptin in regulating energy metabolism, in thermoregulation and in regulating the onset of puberty. We report here that daily injections of recombinant murine leptin in fence lizards (Sceloporus undulatus) produce phenotypic effects similar to those observed when leptin injections are given to mice. Lizards injected with leptin had body temperatures 0.6 degrees C higher, ate 30 % less food and showed a 14 % reduction in activity rates, and females showed a 2. 5-fold increase in resting metabolic rates, compared with lizards injected with vehicle only (phosphate-buffered saline). We also detected native lizard leptin using an immunoassay. Our results indicate that leptin is expressed in ectotherms and may be conserved both functionally and structurally. In the wake of unprecedented research activity on the role of leptin as a cause of, and potential treatment for, human obesity, we believe that other applications of leptin research have been ignored. For example, the response of lizards to leptin injection in our study has important implications for two broad areas of research in evolutionary biology: the evolution of age at first reproduction and of endothermy. We argue that research in these areas, previously limited to comparative approaches, may now benefit from experimental manipulations using leptin.

  7. Sperm motility inversely correlates with seminal leptin levels in idiopathic asthenozoospermia

    PubMed Central

    Guo, Jianhua; Zhao, Yang; Huang, Weiying; Hu, Wei; Gu, Jianjun; Chen, Chuhong; Zhou, Juan; Peng, Yubing; Gong, Min; Wang, Zhong

    2014-01-01

    Background: Asthenozoospermia is one kind cause of male infertility. Nevertheless, no specific etiology can be identified by routine tests in some cases. Recently, it has been shown that leptin plays a critical role in male fertility. However, the link between leptin and sperm motility is yet to be determined. The aim of this study was to explore association between seminal and serum leptin levels and sperm motility in idiopathic asthenozoospermia. Methods: Our study included 79 asthenozoospermic men and 77 normozoospermic men. Semen was assessed by volume, sperm concentration, motility and morphology. Serum gonadotropic and sex hormones were determined by a chemiluminescent assay. The leptin levels in serum and seminal plasma were detected with ELISA. Results: The mean seminal leptin level in asthenozoospermic group was significantly higher than that in control group, but there was no significant difference in the serum leptin levels between these two groups. The serum leptin had no significant correlation with sperm motility. The seminal leptin had significantly negative correlation with sperm progressive motility and serum total testosterone. Conclusions: The findings indicate a pathophysiological relevance of seminal leptin in sperm motility. PMID:25419396

  8. Leptin affects prolactin action on milk protein and fat synthesis in the bovine mammary gland.

    PubMed

    Feuermann, Y; Mabjeesh, S J; Shamay, A

    2004-09-01

    Leptin, a protein hormone produced and secreted predominantly by white adipose tissue, has a critical role in the regulation and coordination of energy metabolism. Identification of leptin in the milk of several mammals, including humans, led us to investigate its presence and regulatory effect in the cow mammary gland. The expression of leptin receptor in tissue culture of lactating mammary gland was augmented approximately 25 times by prolactin, but had no effect on virgin calf mammary tissue. Expression of leptin in tissue culture from mammary glands of lactating cows was enhanced 2.2-fold by prolactin. No effect of prolactin on leptin and leptin receptor expression was found in mammary gland tissue culture from calves. Leptin-enhanced fatty acid synthesis in the presence of prolactin, but had no effect without presence of prolactin. A similar pattern was found in the expression of alpha-casein and beta-lactoglobulin in mammary gland explants from a lactating cow. Our findings indicate that leptin plays an important role in mammary gland lactogenesis, and that the expression of leptin requires the presence of prolactin. PMID:15375055

  9. Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

    PubMed Central

    Chalfant, Madeleine C.; Gorden, Lee D.

    2015-01-01

    Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration. PMID:25919692

  10. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway.

    PubMed

    Martin, Aline; David, Valentin; Malaval, Luc; Lafage-Proust, Marie-Hélène; Vico, Laurence; Thomas, Thierry

    2007-07-01

    Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies.

  11. Hypertension in obesity: is leptin the culprit?

    PubMed

    Simonds, Stephanie E; Cowley, Michael A

    2013-02-01

    The number of obese or overweight humans continues to increase worldwide. Hypertension is a serious disease that often develops in obesity, but it is not clear how obesity increases the risk of hypertension. However, both obesity and hypertension increase the risk of cardiovascular diseases (CVD). In this review, we examine how obesity may increase the risk of developing hypertension. Specifically, we discuss how the adipose-derived hormone leptin influences the sympathetic nervous system (SNS), through actions in the brain to elevate energy expenditure (EE) while also contributing to hypertension in obesity.

  12. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice

    NASA Technical Reports Server (NTRS)

    Winters, B.; Mo, Z.; Brooks-Asplund, E.; Kim, S.; Shoukas, A.; Li, D.; Nyhan, D.; Berkowitz, D. E.

    2000-01-01

    Obesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.

  13. Mechanisms involved in p53 downregulation by leptin in trophoblastic cells.

    PubMed

    Toro, Ayelén Rayen; Pérez-Pérez, Antonio; Corrales Gutiérrez, Isabel; Sánchez-Margalet, Víctor; Varone, Cecilia Laura

    2015-11-01

    Leptin, a 16-kDa polypeptide hormone, is produced by the adipocyte and can also be synthesized by placenta. We previously demonstrated that leptin promotes proliferation and survival in placenta, in part mediated by the p53 pathway. In this work, we investigated the mechanisms involved in leptin down-regulation of p53 level. The human first trimester cytotrophoblastic Swan-71 cell line and human placental explants at term were used. In order to study the late phase of apoptosis, triggered by serum deprivation, experiments of DNA fragmentation were carried out. Exogenous leptin added to human placental explants, showed a decrease on DNA ladder formation and MAPK pathway is involved in this leptin effect. We also found that under serum deprivation condition, leptin decreases p53 levels and the inhibitory leptin effect is lost when cells were pretreated with 50 μM PD98059 or 10 μM LY29004; or were transfected with dominant negative mutants of intermediates of these pathways, suggesting that MAPK and PI3K signaling pathways are necessaries for leptin action. Additionally, leptin diminished Ser-46 p53 phosphorylation and this effect in placental explants was mediated by the activation of MAPK and PI3K pathways. Finally, in order to assess leptin effect on p53 half-life experiments with cycloheximide were performed and MDM-2 expression was analyzed. Leptin diminished p53 half-life and up-regulated MDM-2 expression. In summary, we provided evidence suggesting that leptin anti-apoptotic effect is mediated by MAPK and PI3K pathways.

  14. [ROLE OF LEPTIN IN THE FORMATION OF SECONDARY AMENORRHEA IN ADOLESCENT GIRLS].

    PubMed

    Levenets, S A; Nachotova, T A; Kashkalda, D A

    2015-01-01

    In order to understand the role of leptin in the formation of secondary amenorrhea (SA) during puberty, 78 girls aged from 13 to 17 years with SA and 74 girls of the same age with regular menstrual cycle have been examined with the estimation of body mass index (BMI) and hormonal/metabolic state. The obtained data show a strong connection between leptin level, BMI and parameters of energetic metabolic state (insulin; HOMA index); regression analysis results indicated the participation of leptin in steroidogenesis. Odds ratio (OR) values indicated an important role of leptin in the formation of SA during body weight deficit and normal BMI. It has been found that various clinical types of SA have different patterns of leptin influence. PMID:27089723

  15. A novel role of the checkpoint kinase ATR in leptin signaling.

    PubMed

    Ericson, Elke; Wennberg Huldt, Charlotte; Strömstedt, Maria; Brodin, Peter

    2015-09-01

    In a world with increasing incidences of obesity, it becomes critical to understand the detailed regulation of appetite. To identify novel regulators of the signaling mediated by one of the key hormones of energy homeostasis, leptin, we screened a set of compounds for their effect on the downstream Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Interestingly, cells exposed to inhibitors of the Ataxia Telangiectasia and RAD3-related protein ATR increased their leptin dependent STAT3 activity. This was due to failure of the cells to induce the negative feedback mediator Suppressor of Cytokine Signaling 3 (SOCS3), suggesting that ATR has a previously unknown role in the negative feedback regulation of leptin signaling. This is an important finding not only because it sheds light on additional genes involved in leptin signaling, but also because it brings forward a new potential therapeutic intervention point for increasing leptin signaling in obese individuals.

  16. Taste bud leptin: sweet dampened at initiation site.

    PubMed

    Travers, Susan P; Frank, Marion E

    2015-05-01

    The intriguing observation that leptin decreases sweet-evoked peripheral gustatory responses has aroused much interest (Kawai K, Sugimoto K, Nakashima K, Miura H, Ninomiya Y. 2000. Leptin as a modulator of sweet taste sensitivities in mice. Proc Natl Acad Sci U S A. 97(20):11044-11049.) due to its implied importance in controlling appetite. The effects of this anorexic hormone, however, appear more conditional than originally believed. In this issue of Chemical Senses, a careful study by Glendinning and colleagues, find no effects of leptin on sweet-evoked chorda tympani responses, whereas an equally careful study by Meredith and colleagues, find decreased release of ATP and increased release of 5-HT from taste buds in response to sweet stimuli.

  17. A short form of leptin receptor performs signal transduction.

    PubMed

    Murakami, T; Yamashita, T; Iida, M; Kuwajima, M; Shima, K

    1997-02-01

    The obese (ob) gene product, leptin, a peptide hormone, which is synthesized in adipocytes, is a satiety factor and is involved in the control of body weight via the regulation of energy homeostasis. Several alternate spliced isoforms (a-e, as well as others) of the leptin receptor (OBR) have been cloned, all of which, except for OBRe (soluble form), contain a single transmembrane domain. They share the same extracellular domain, with homology to the class I cytokine receptor family. The OBRb, which has longest cytoplasmic domain, is expressed in high levels in the hypothalamus and is thought to be the only isoform capable of signal transmission. Herein, we report the mRNA expression of immediate early genes, c-fos, c-jun and jun-B, which are induced by leptin addition, not only in CHO cells expressing the OBRb, but also in cells expressing one of the short form receptors, OBRa.

  18. Ontogeny of the long form of leptin receptor gene expression in the porcine ovarian follicles.

    PubMed

    Smolinska, N; Kaminski, T; Siawrys, G; Przala, J

    2013-01-01

    Leptin is a polypeptide hormone produced predominantly in adipocytes. It has been found to be implicated in the regulation of satiety and energy homeostasis. A role for leptin in reproduction was later suggested by findings that this hormone may be involved in the regulation of the hypothalamic-pituitary-gonadal axis via endocrine, paracrine and/or autocrine pathways. The objective of the study was to investigate the ontogeny of the long isoform of leptin receptor (OB-Rb) gene in porcine ovarian follicles. The expression of OB-Rb gene was detected in porcine primordial, primary, secondary and antral follicles by in situ hybridization. In summary, our data suggest that leptin might have a direct effect on porcine follicles and plays an important role in the follicular development.

  19. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish

    PubMed Central

    Michel, Maximilian; Page-McCaw, Patrick S.; Chen, Wenbiao; Cone, Roger D.

    2016-01-01

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals. PMID:26903647

  20. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish.

    PubMed

    Michel, Maximilian; Page-McCaw, Patrick S; Chen, Wenbiao; Cone, Roger D

    2016-03-15

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.

  1. A mathematical model of leptin resistance.

    PubMed

    Jacquier, Marine; Soula, Hédi A; Crauste, Fabien

    2015-09-01

    Obesity is often associated with leptin resistance, which leads to a physiological system with high leptin concentration but unable to respond to leptin signals and to regulate food intake. We propose a mathematical model of the leptin-leptin receptors system, based on the assumption that leptin is a regulator of its own receptor activity, and investigate its qualitative behavior. Based on current knowledge and previous models developed for body weight dynamics in rodents, the model includes the dynamics of leptin, leptin receptors and the regulation of food intake and body weight. It displays two stable equilibria, one representing a healthy state and the other one an obese and leptin resistant state. We show that a constant leptin injection can lead to leptin resistance and that a temporal variation in some parameter values influencing food intake can induce a change of equilibrium and a pathway to leptin resistance and obesity.

  2. Leptin Is an Anti-Apoptotic Effector in Placental Cells Involving p53 Downregulation

    PubMed Central

    Toro, Ayelén Rayen; Maymó, Julieta Lorena; Ibarbalz, Federico Matías; Pérez, Antonio Pérez; Maskin, Bernardo; Faletti, Alicia Graciela; Margalet, Víctor Sánchez; Varone, Cecilia Laura

    2014-01-01

    Leptin, a peripheral signal synthetized by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may work as an autocrine hormone. We have previously demonstrated that leptin promotes proliferation and survival of trophoblastic cells. In the present work, we aimed to study the molecular mechanisms that mediate the survival effect of leptin in placenta. We used the human placenta choriocarcinoma BeWo and first trimester Swan-71 cell lines, as well as human placental explants. We tested the late phase of apoptosis, triggered by serum deprivation, by studying the activation of Caspase-3 and DNA fragmentation. Recombinant human leptin added to BeWo cell line and human placental explants, showed a decrease on Caspase-3 activation. These effects were dose dependent. Maximal effect was achieved at 250 ng leptin/ml. Moreover, inhibition of endogenous leptin expression with 2 µM of an antisense oligonucleotide, reversed Caspase-3 diminution. We also found that the cleavage of Poly [ADP-ribose] polymerase-1 (PARP-1) was diminished in the presence of leptin. We analyzed the presence of low DNA fragments, products from apoptotic DNA cleavage. Placental explants cultivated in the absence of serum in the culture media increased the apoptotic cleavage of DNA and this effect was prevented by the addition of 100 ng leptin/ml. Taken together these results reinforce the survival effect exerted by leptin on placental cells. To improve the understanding of leptin mechanism in regulating the process of apoptosis we determined the expression of different intermediaries in the apoptosis cascade. We found that under serum deprivation conditions, leptin increased the anti-apoptotic BCL-2 protein expression, while downregulated the pro-apoptotic BAX and BID proteins expression in Swan-71 cells and placental explants. In both models leptin augmented BCL-2/BAX ratio. Moreover we have demonstrated that p53, one of the key cell cycle-signaling proteins, is

  3. Serum leptin levels in preterm, healthy and sick-term newborns.

    PubMed

    Su, Pen-Hua; Wang, Shu-Li; Chen, Jia-Yuh; Lai, Cheng-Pin Chang; Jian, Shu-Hua

    2002-01-01

    Leptin, a hormone that signals the brain about the status of body (fat) energy stores, has recently been shown to play a role in the regulation of several hypothalamic pituitary axes, including the growth hormone axis. To investigate a potential association of serum leptin concentrations and clinical condition in preterm, sick term and healthy term newborns, serum leptin concentrations were evaluated in 104 newborns. Twenty-eight of them were healthy term (18 males and 10 females; gestational age, 37-42 weeks), 21 were sick term (12 males and 9 females; gestational age, 37-42 weeks) and 55 were preterm neonates (35 males and 20 females; gestational age: 26-37 weeks). Leptin values correlate positively with birth weight, birth length, head circumference, waist circumference, hip circumference, body surface, weight/length ratio, and gestational age (r = 0.38, 0.42, 0.29, 0.21, 0.29, 0.40, 0.31 and 0.28), respectively. The concentrations of leptin are statistically significantly higher (p < 0.05) in term neonates (3.02 +/- 2.94 ng/ml) than preterm neonates (1.93 +/- 2.21 ng/ml). Female infants also have significantly higher (p < 0.05) serum leptin values than male infants in preterm and healthy term groups. We also found leptin present in venous blood after 26 weeks of gestation. PMID:12607479

  4. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.

    PubMed

    Chan, Jean L; Heist, Kathleen; DePaoli, Alex M; Veldhuis, Johannes D; Mantzoros, Christos S

    2003-05-01

    To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone-IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity.

  5. Association of Increased Serum Leptin with Ameliorated Anemia and Malnutrition in Stage 5 Chronic Kidney Disease Patients after Parathyroidectomy

    PubMed Central

    Jiang, Yao; Zhang, Jingjing; Yuan, Yanggang; Zha, Xiaoming; Xing, Changying; Shen, Chong; Shen, Zhixiang; Qin, Chao; Zeng, Ming; Yang, Guang; Mao, Huijuan; Zhang, Bo; Yu, Xiangbao; Sun, Bin; Ouyang, Chun; Xu, Xueqiang; Ge, Yifei; Wang, Jing; Zhang, Lina; Cheng, Chen; Yin, Caixia; Zhang, Jing; Chen, Huimin; Ma, Haoyang; Wang, Ningning

    2016-01-01

    Leptin is an adipokine that regulates various metabolism, but its association with secondary hyperparathyroidism (SHPT), a clinical manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD), remains obscure. Parathyroidectomy (PTX) is recommended for severe SHPT patients. Here, the associations between circulating leptin and clinical characteristics in CKD patients were investigated. Effects of PTX on leptin production were analyzed in vivo and in vitro. Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with body mass index (BMI) <23 kg/m2. Serum leptin was related to anemia, albumin, and bone metabolism disorders in CKD patients. Lower intact parathyroid hormone (PTH) was related with higher leptin in PTX patients group. Severe SHPT inhibited uremia-enhanced leptin production in 3T3-L1 adipocytes, which was attenuated after PTX. High levels of PTH were found to reduce Akt phosphorylation and leptin production in vitro but high levels of calcium and phosphorus were not. Successful PTX was found to improve anemia and malnutrition in severe SHPT patients, and this was correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes. These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD. PMID:27307101

  6. Pathophysiological role of leptin in obesity-related hypertension.

    PubMed

    Aizawa-Abe, M; Ogawa, Y; Masuzaki, H; Ebihara, K; Satoh, N; Iwai, H; Matsuoka, N; Hayashi, T; Hosoda, K; Inoue, G; Yoshimasa, Y; Nakao, K

    2000-05-01

    To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA(y) mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by alpha(1)-adrenergic, beta-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an alpha-melanocyte-stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKA(y) mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the A(y) allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the A(y) allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKA(y) mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension.

  7. Pathophysiological role of leptin in obesity-related hypertension

    PubMed Central

    Aizawa-Abe, Megumi; Ogawa, Yoshihiro; Masuzaki, Hiroaki; Ebihara, Ken; Satoh, Noriko; Iwai, Hidenori; Matsuoka, Naoki; Hayashi, Tatsuya; Hosoda, Kiminori; Inoue, Gen; Yoshimasa, Yasunao; Nakao, Kazuwa

    2000-01-01

    To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKAy mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by α1-adrenergic, β-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an α-melanocyte–stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKAy mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the Ay allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the Ay allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKAy mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension. PMID:10791999

  8. [Serum leptin concentration and some lipid parameters in vegetarian children].

    PubMed

    Laskowska-Klita, Teresa; Ambroszkiewicz, Jadwiga; Klemarczyk, Witold

    2004-04-01

    Leptin, a hormone from adipose tissue, regulates feeding behavior, satiation rate, energy expenditure and also plays an important role in maturation and reproduction. Recent studies support the concept that several factors such as a diet may influence on leptin levels. The aim of this study was to investigate serum concentration of leptin and lipids status in prepubertal children aged from 2 to 10 years with two different nutritional habits: vegetarian (n = 24) and omnivorous diet (n = 20). Serum leptin concentration was determined by immunoenzymeassay (ELISA). Serum lipids (cholesterol, HDL- and LDL-cholesterol, triglyceride) were measured by enzymatic and apolipoproteins by immunoturbidimetric methods. We noticed that in vegetarian diet there is a high rate of fiber (nearly twice as high as in omnivorous diet) and polyunsaturated acids (35% as much). In our study vegetarian children had lower total cholesterol and cholesterol in fractions HDL and LDL than meat eaters did. Also the apolipoproteins levels in vegetarian children were significantly below that of nonvegetarians. There is no differences in triglyceride concentration between the two groups of children. The mean serum leptin level in vegetarian children was significantly lower (3.1 +/- 1.2 ng/mL) as compared with the omnivores (5.6 +/- 2.1 ng/mL) (p < 0.0001).

  9. Leptin Induces a Novel Form of NMDA Receptor-Dependent LTP at Hippocampal Temporoammonic-CA1 Synapses(1,2,3).

    PubMed

    Luo, Xiao; McGregor, Gemma; Irving, Andrew J; Harvey, Jenni

    2015-01-01

    It is well documented that the hormone leptin regulates many central functions and that hippocampal CA1 pyramidal neurons are a key target for leptin action. Indeed, leptin modulates excitatory synaptic transmission and synaptic plasticity at the Schaffer-collateral input to CA1 neurons. However the impact of leptin on the direct temporoammonic (TA) input to CA1 neurons is not known. Here we show that leptin evokes a long-lasting increase [long-term potentiation (LTP)] in excitatory synaptic transmission at TA-CA1 synapses in rat juvenile hippocampus. Leptin-induced LTP was NMDA receptor-dependent and specifically involved the activation of GluN2B subunits. The signaling pathways underlying leptin-induced LTP involve the activation of phosphoinositide 3-kinase, but were independent of the ERK signaling cascade. Moreover, insertion of GluA2-lacking AMPA receptors was required for leptin-induced LTP as prior application of philanthotoxin prevented the effects of leptin. In addition, synaptic-induced LTP occluded the persistent increase in synaptic efficacy induced by leptin. In conclusion, these data indicate that leptin induces a novel form of NMDA receptor-dependent LTP at juvenile TA-CA1 synapses, which has important implications for the role of leptin in modulating hippocampal synaptic function in health and disease. PMID:26464986

  10. Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells.

    PubMed

    Shen, Minqian; Shi, Haifei

    2016-01-01

    Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 β-estradiol (E2), estrogen receptor-α (ER-α) selective agonist PPT, ER-β selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-β mRNA, and leptin treatment increased ER-β expression. E2 suppressed leptin-induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-β. E2 also enhanced ERK via activating ER-α and GPER and activated p38/MAPK via activating ER-β. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-β, and increasing ERK by activating ER-α and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients. PMID:26982332

  11. An updated view of leptin on implantation and pregnancy: a review.

    PubMed

    Herrid, M; Palanisamy, S K A; Ciller, U A; Fan, R; Moens, P; Smart, N A; McFarlane, J R

    2014-01-01

    The hormone leptin, which is thought to be primarily produced by adipose tissue, is a polypeptide that was initially characterized by its ability to regulate food intake and energy metabolism. Leptin appears to signal the status of body energy stores to the brain, resulting in the regulation of food intake and whole-body energy expenditure. Subsequently, it was recognized as a cytokine with a wide range of peripheral actions and is involved in the regulation of a number of physiological systems including reproduction. In the fed state, leptin circulates in the plasma in proportion to body adiposity in all species studied to date. However other factors such as sex, age, body mass index (BMI), sex steroids and pregnancy may also affect leptin levels in plasma. In pregnant mice and humans, the placenta is also a major site of leptin expression. Leptin circulates in biological fluids both as free protein and in a form that is bound to the soluble isoform of its receptor or other binding proteins such as one of the immunoglobulin superfamily members Siglec-6 (OB-BP1). Although the actions of leptin in the control of reproductive function are thought to be exerted mainly via the hypothalamic-pituitary-gonadal axis, there have also been reports of local direct effects of leptin at the peripheral level, however, these data appear contradictory. Therefore, there is a need to summarize the current status of research outcomes and analyze the possible reasons for differing results and thus provide researchers with new insight in designing experiments to investigate leptin effect on reproduction. Most importantly, our recent experimental data suggesting that reproductive performance is improved by decreasing concentrations of peripheral leptin was unexpected and cannot be explained by hypotheses drawn from the experiments of excessive exogenous leptin administration to normal animals or ob/ob mice.

  12. Preventing leptin resistance by blocking angiotensin II AT1 receptors in diet-induced obese rats

    PubMed Central

    Müller-Fielitz, Helge; Lau, Margot; Geißler, Cathleen; Werner, Lars; Winkler, Martina; Raasch, Walter

    2015-01-01

    Background and Purpose AT1 receptor blockers (ARBs) represent an approach for treating metabolic syndrome due to their potency in reducing hypertension, body weight and onset of type 2 diabetes. The mechanism underlying ARB-induced weight loss is still unclear. Experimental Approach Leptin resistance tests (LRTs) in diet-induced obese or lean rats were conducted to determine whether telmisartan (8 mg·kg−1·day−1, 14 days) enhances leptin sensitivity. Phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) staining was performed in hypothalami to determine leptin transport across the blood–brain barrier. Key Results Telmisartin reduced weight gain, food intake and plasma leptin but blood pressure remained unchanged. The 24 h profiles of plasma leptin after saline injections were similar in controls and telmisartan-treated rats, but after leptin injections were higher in controls and slightly lower in telmisartan-treated animals. After telmisartan, energy intake during LRT was lower in leptin-than in saline-pretreated rats, but remained unchanged in controls, irrespectively of whether rats received saline or leptin. Leptin minimized the gain in body weight during LRT in telmisartan-treated rats as compared with saline-treated animals. pSTAT3 staining was reduced in cafeteria diet-fed rats as compared with chow-fed rats but this was normalized by telmisartan. Telmisartin reduced hypothalamic mRNA levels of the orexigenic peptides melanin-concentrating hormone and prepro-orexin. Conclusions and Implications Rats fed a cafeteria diet develop leptin resistance after 2 weeks. Leptin sensitivity was preserved by telmisartan treatment even in rats fed a cafeteria diet. This pleiotropic effect is not related to the hypotensive action of telmisartan. PMID:25258168

  13. Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells

    PubMed Central

    Shen, Minqian; Shi, Haifei

    2016-01-01

    Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 β-estradiol (E2), estrogen receptor-α (ER-α) selective agonist PPT, ER-β selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-β mRNA, and leptin treatment increased ER-β expression. E2 suppressed leptin-induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-β. E2 also enhanced ERK via activating ER-α and GPER and activated p38/MAPK via activating ER-β. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-β, and increasing ERK by activating ER-α and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients. PMID:26982332

  14. Time-dependent effects of starvation on serum, pituitary and hypothalamic leptin levels in rats.

    PubMed

    Vujovic, P; Lakic, I; Laketa, D; Jasnic, N; Djurasevic, S F; Cvijic, G; Djordjevic, J

    2011-01-01

    Leptin is produced by white adipose tissue and other cell types and is involved in both short- and long-term appetite control. Here we studied effects of starvation on serum, pituitary and hypothalamic levels of leptin during 72 h period. Each of the starved groups was sacrificed simultaneously with the group of ad libitum fed animals. The progression of the discrete starvation response phases was monitored by testing the blood glucose, free fatty acid, urea and corticosterone levels. Starvation caused biphasic increase in corticosterone and free fatty acid levels, and significant but transient decrease in urea and glucose levels. Starvation also abolished diurnal rhythm of changes in leptin concentrations in serum and hypothalamic and pituitary tissues. Only 6 h starving period was sufficient to lock serum leptin at low levels, whereas 12 h were needed to silence leptin production/secretion in hypothalamus for the whole examined period. In contrast, leptin production by pituitary tissues of starved animals required 24 h to reach minimum, followed by full recovery by the end of starvation period. These results indicate the tissue specific pattern of leptin release and suggest that the locally produced leptin could activate its receptor in pituitary cells independently of serum levels of this hormone.

  15. A role for the central histaminergic system in the leptin-mediated increase in cardiovascular dynamics.

    PubMed

    Rao, Sumangala P; Dunbar, Joseph C

    2005-01-15

    The central nervous system (CNS) histaminergic neurons have been shown to regulate feeding behavior and are a target of leptin in the brain. The present study aimed to examine the involvement of the histaminergic system in the leptin-mediated regulation of cardiovascular dynamics. We investigated the cardiovascular responses to the CNS administration of histamine, leptin and alpha-melanocyte stimulating hormone (alpha-MSH) both in the presence and absence of the histamine H1 antagonist, chlorpheniramine. The intracerebroventricular (i.c.v.) administration of histamine resulted in an immediate increase in both mean arterial pressure (MAP) and heart rate (HR) and vasoconstricted the iliac, renal and superior mesenteric vessels. The i.c.v. pretreatment with chlorpheniramine attenuated the histamine-induced increase in MAP, HR and decreased vascular conductance. The i.c.v. administration of leptin increased MAP and HR and decreased vascular conductance. The i.c.v. pretreatment with chlorpheniramine decreased the leptin-induced increase in MAP and the leptin-mediated iliac vasoconstriction. The i.c.v. administration of alpha-MSH also increased MAP, HR and decreased vascular conductance. However, pretreatment with chlorpheniramine did not influence the central alpha-MSH-mediated increase in MAP, HR and decreased vascular conductance. These results indicate that the central histaminergic system mediated by H1 receptors have a role in the central signaling pathway and is involved in leptin's regulation of cardiovascular dynamics. It appears that leptin directly or indirectly stimulates histaminergic neurons that lead to increased cardiovascular activity.

  16. Evaluation of Serum Leptin Levels and Growth in Patients with β-Thalassaemia Major

    PubMed Central

    Al-Naama, Lamia Mustafa; Hassan, Meaad Kadum; Abdul Karim, Muhannad Maki

    2016-01-01

    Background. Iron deposition in the body can damage the endocrine glands of patients with β-thalassaemia major (β-TM). Leptin plays a key role in the regulation of appetite, body fat mass, and endocrine function. Objectives. This study aimed to evaluate the relationship between serum leptin and growth and pubertal development in patients with β-TM, as well as whether serum leptin can predict growth retardation and delayed puberty in these patients. Methods. Fifty β-TM patients (aged 8–20 years) and 75 age-matched healthy controls were recruited. Anthropometric data and sexual maturity ratings were assessed. Serum leptin was measured by ELISA. Results. Serum leptin levels were significantly lower in patients with β-TM than in healthy individuals (P < 0.001). Leptin levels were also significantly reduced in female patients with short stature (P < 0.002) and in patients who displayed delayed puberty (P = 0.032) compared to those with normal stature who had reached puberty. The sensitivity of leptin for predicting short stature and delayed puberty among patients was 84.6% and 92.3%, respectively. Conclusion. Low serum leptin is sensitive to predict short stature and significant in β-TM females only. This link could thus be used as a guide for further therapeutic or hormonal modulation. PMID:27088012

  17. Postnatal leptin is necessary for maturation of numerous organs in newborn rats

    PubMed Central

    Larcher, Thibaut; Gertler, Arieh; Abdennebi-Najar, Latifa

    2011-01-01

    The postnatal leptin surge, described particularly in rodents, has been demonstrated to be crucial for hypothalamic maturation and brain development. In the present study, the possible general effects of this hormone on maturation of numerous peripheral organs have been explored. To test this hypothesis, we used a leptin antagonist (L39A/D40A/F41A) to investigate the effects of the blockage of postnatal leptin action on neonatal growth and maturation of organs involved in metabolism regulation, reproduction and immunity. For that purpose, newborn female pups were subcutaneously injected from days 2–13 with either saline or leptin antagonist and sacrificed at weaning. Organs were submitted to histological and immunohistochemical analyses. Leptin antagonist treatment clearly impaired the maturation of pancreas, kidney, thymus and ovary. All these alterations, at the organ level, occurred without changes in the whole-body mass of the animals. Leptin antagonist treatment induced: (1) a reduction in β cell area and a concomitant increase of α cells in Langherans islets in the pancreas, (2) a reduction in the number of glomeruli and a persistence of immature glomeruli in kidney, (3) an increase in the thymic cortical layer thickness, reflecting an unmatured stage, (4) a drastic reduction of the pool of primordial follicles, in ovaries. All these results strongly argue for a crucial role of leptin for the achievement of organ maturation, opening new perspectives in the field of leptin physiology and organ development. PMID:21378499

  18. Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis

    PubMed Central

    Rachakonda, Vikrant; Borhani, Amir A.; Dunn, Michael A.; Andrzejewski, Margaret; Martin, Kelly; Behari, Jaideep

    2016-01-01

    Background and Aims Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition. Design In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition. Results Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition. Conclusions Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease. PMID:27583675

  19. Roles of leptin in bone metabolism and bone diseases.

    PubMed

    Chen, Xu Xu; Yang, Tianfu

    2015-09-01

    Adipose tissue has been more accepted as an active contributor to whole body homeostasis, rather than just a fat depot, since leptin, a 16 kDa protein, was discovered as the product of the obese gene in 1994. With more and more studies conducted on this hormone, it has been shown that there is a close relationship between adipose tissue and bone, which have important effects on each other. Bone is the source of many hormones, such as osteocalcin, that can affect energy metabolism and then the anabolism or catabolism of fat tissue. In contrast, the adipose tissue synthesizes and releases a series of adipokines, which are involved in bone metabolism through direct or indirect effects on bone formation and resorption. Interestingly, leptin, one of the most important cytokines derived from fat tissue, seems to account for the largest part of effects on bone, through direct or indirect involvement in bone remodeling and by playing a significant role in many bone diseases, such as osteoporosis, osteoarthritis, rheumatic arthritis, bone tumors and even fractures. In this review, we will discuss the progress in leptin research, particularly focusing on the roles of leptin in bone diseases.

  20. Cross-talk between reproduction and energy homeostasis: central impact of estrogens, leptin and kisspeptin signaling

    PubMed Central

    Nestor, Casey C; Kelly, Martin J.; Rønnekleiv, Oline K.

    2016-01-01

    The central nervous system receives hormonal cues (e.g., estrogens and leptin, among others) that influence reproduction and energy homeostasis. 17β-estradiol (E2) is known to regulate gonadotropin-releasing hormone (GnRH) secretion via classical steroid signaling and rapid non-classical membrane-initiated signaling. Because GnRH neurons are void of leptin receptors, the actions of leptin on these neurons must be indirect. Although it is clear that the arcuate nucleus of the hypothalamus is the primary site of overlap between these two systems, it is still unclear which neural network(s) participate in the cross-talk of E2 and leptin, two hormones essential for reproductive function and metabolism. Herein we review the progress made in understanding the interactions between reproduction and energy homeostasis by focusing on the advances made to understand the cellular signaling of E2 and leptin on three neural networks: kisspeptin, pro-opiomelanocortin (POMC) and neuropeptide Y (NPY). Although critical in mediating the actions of E2 and leptin, considerable work still remains to uncover how these neural networks interact in vivo. PMID:25372735

  1. Menstrual cycle hormones, food intake, and cravings

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Food craving and intake are affected by steroid hormones during the menstrual cycle, especially in the luteal phase, when craving for certain foods has been reported to increase. However, satiety hormones such as leptin have also been shown to affect taste sensitivity, and therefore food ...

  2. Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen

    PubMed Central

    Shi, Zhigang; Brooks, Virginia L

    2015-01-01

    Key points Leptin increases sympathetic nerve activity (SNA) in males, which contributes to obesity-induced hypertension; however, whether leptin is equally effective in females is unknown. We report that leptin does increase SNA and heart rate in female rats; however, for lumbar and renal SNA, this action is only evident in pro-oestrus and in oestrogen-treated ovariectomized rats, but not in ovariectomized or dioestrus rats. Leptin increases SNA and heart rate similarly in male and pro-oestrus female rats; however, leptin increases arterial pressure only in males. Blockade of MC3/4 receptors in the paraventricular nucleus (PVN) with SHU9119 decreases SNA in leptin-treated pro-oestrus rats, suggesting that leptin increases SNA in part by increasing α-melanocyte-stimulating hormone drive of PVN presympathetic neurons. Our data establish sex differences in leptin's effects to increase SNA and arterial pressure, which emphasizes the need for enhanced recognition and investigation of sex differences in obesity-induced sympathoexcitation and hypertension. Abstract Obesity and hypertension are commonly associated, and activation of the sympathetic nervous system is considered to be a major contributor, at least in part due to the central actions of leptin. However, while leptin increases sympathetic nerve activity (SNA) in males, whether leptin is equally effective in females is unknown. Here, we show that intracerebroventricular (i.c.v.) leptin increases lumbar (LSNA) and renal (RSNA) SNA and baroreflex control of LSNA and RSNA in α-chloralose anaesthetized female rats, but only during pro-oestrus. In contrast, i.c.v. leptin increased basal and baroreflex control of splanchnic SNA (SSNA) and heart rate (HR) in rats in both the pro-oestrus and dioestrus states. The effects of leptin on basal LSNA, RSNA, SSNA and HR were similar in males and pro-oestrus females; however, i.c.v. leptin increased mean arterial pressure (MAP) only in males. Leptin did not alter LSNA or HR

  3. Free leptin, bound leptin, and soluble leptin receptor in normal and diabetic pregnancies.

    PubMed

    Lewandowski, K; Horn, R; O'Callaghan, C J; Dunlop, D; Medley, G F; O'Hare, P; Brabant, G

    1999-01-01

    We measured serum levels of free leptin, bound leptin, and soluble leptin receptor by specific RIA methods in 20 normal and 19 insulin-dependent diabetes mellitus subjects at 20 and 30 weeks gestation and postpartum, and analyzed the data using hierarchical statistical models. Total leptin levels rise from 20-30 weeks gestation (688 +/- 58 to 785 +/- 62 pmol/L, mean +/- SEM; P = 0.009). There is a significant postpartum fall to 445 +/- 47 pmol/L (P < 0.001). This rise is caused by the rise in the bound leptin levels, as there is no significant change in free leptin levels between 20 and 30 weeks (P = 0.17). There is a significant postpartum fall in free leptin levels (P < 0.001). Insulin requirements rise in the third trimester, but despite this there was no significant difference in free or bound leptin levels between the normal and diabetic subjects at any stage [free leptin, 223 +/- 35 and 266 +/- 24, 237 +/- 45 and 223 +/- 27, and 109 +/- 16 and 104 +/- 24 (P = 0.34); bound leptin, 410 +/- 73 and 428 +/- 54, 501 +/- 78 and 562 +/- 71, and 330 +/- 47 and 271 +/- 46 (P = 0.84); for normals and diabetics at 20 and 30 weeks gestation and postpartum, respectively]. Diabetic subjects, however, had significantly higher soluble leptin receptor levels at all stages (P < 0.001), which rose further in the third trimester from 3742 +/- 268 (mean +/- SEM) to 4134 +/- 239 pmol/L, whereas in the normal group there was a fall from 3149 +/- 169 to 2712 +/- 123 (P = 0.05). There is a linear relationship between the soluble leptin receptor levels and the body mass index in the diabetic group only. We conclude that there is no significant difference in free or bound leptin levels between the normal and insulin-dependent diabetic subjects either during pregnancy or postpartum, but female insulin-dependent diabetic subjects have significantly higher soluble leptin receptor levels. We speculate that high soluble leptin receptor levels might be implicated in the development of the

  4. Effects of acute changes in neonatal leptin levels on food intake and long-term metabolic profiles in rats.

    PubMed

    Granado, Miriam; García-Cáceres, Cristina; Fuente-Martín, Esther; Díaz, Francisca; Mela, Virginia; Viveros, Maria-Paz; Argente, Jesús; Chowen, Julie A

    2011-11-01

    In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

  5. Leptin mediates seasonal variation in some but not all symptoms of sickness in Siberian hamsters.

    PubMed

    Carlton, Elizabeth D; Demas, Gregory E

    2014-11-01

    Many seasonally breeding species, including Siberian hamsters (Phodopus sungorus), exhibit seasonal variation in sickness responses. One hypothesis regarding the mechanism of this variation is that sickness intensity tracks an animal's energetic state, such that sickness is attenuated in the season that an animal has the lowest fat stores. Energetic state may be signaled via leptin, an adipose hormone that provides a signal of fat stores. Siberian hamsters respond to extended housing in short, winter-like days by reducing fat stores and leptin levels, relative to those housed in long, summer-like days. Sickness responses are also attenuated in short-day hamsters as compared to long-day hamsters. We hypothesized that leptin provides a physiological signal by which seasonally breeding animals modulate sickness responses, such that animals with higher leptin levels show increased sickness intensity. To test this, we provided short-day hamsters with a long-day-like leptin signal and assessed their responses to lipopolysaccharide (LPS), a sickness-inducing antigen. We compared these responses to short-day vehicle-, long-day vehicle-, and long-day leptin-treated hamsters. Unexpectedly, LPS induced a hypothermic response (rather than fever) in all groups. Short-day vehicle-treated hamsters exhibited the greatest LPS-induced hypothermia, and leptin treatment attenuated this response, making hypothermia more long-day-like. Contrary to our hypothesis, short-day leptin-treated hamsters showed the least pronounced LPS-induced anorexia among all groups. These results suggest that leptin may mediate some but not all aspects of seasonal sickness variation in this species. Future studies should be targeted at determining roles of other energetic hormones in regulating seasonal sickness response variation.

  6. Leptin mediates seasonal variation in some but not all symptoms of sickness in Siberian hamsters

    PubMed Central

    Carlton, Elizabeth D.; Demas, Gregory E.

    2014-01-01

    Many seasonally breeding species, including Siberian hamsters (Phodopus sungorus), exhibit seasonal variation in sickness responses. One hypothesis regarding the mechanism of this variation is that sickness intensity tracks an animal's energetic state, such that sickness is attenuated in the season that an animal has the lowest fat stores. Energetic state may be signaled via leptin, an adipose hormone that provides a signal of fat stores. Siberian hamsters respond to extended housing in short, winter-like days by reducing fat stores and leptin levels, relative to those housed in long, summer-like days. Sickness responses are also attenuated in short-day hamsters as compared to long-day hamsters. We hypothesized that leptin provides a physiological signal by which seasonally breeding animals modulate sickness responses, such that animals with higher leptin levels show increased sickness intensity. To test this, we provided short-day hamsters with a long-day-like leptin signal and assessed their responses to lipopolysaccharide (LPS), a sickness-inducing antigen. We compared these responses to short-day vehicle-, long-day vehicle-, and long-day leptin-treated hamsters. Unexpectedly, LPS induced a hypothermic response (rather than fever) in all groups. Short-day vehicle-treated hamsters exhibited the greatest LPS-induced hypothermia, and leptin treatment attenuated this response, making hypothermia more long-day-like. Contrary to our hypothesis, short-day leptin-treated hamsters showed the least pronounced LPS-induced anorexia among all groups. These results suggest that leptin may mediate some but not all aspects of seasonal sickness variation in this species. Future studies should be targeted at determining roles of other energetic hormones in regulating seasonal sickness response variation. PMID:25461974

  7. Evaluation of Salivary Leptin Levels in Healthy Subjects and Patients with Advanced Periodontitis

    PubMed Central

    Khorsand, Afshin; Bayani, Mojtaba; Torabi, Sepehr; Kharrazifard, Mohammad Javad; Mohammadnejhad, Fatemeh

    2016-01-01

    Objectives: Leptin is a hormone-like protein produced by the adipose tissue. It plays an important role in protection of host against inflammation and infection. Some studies have reported changes in leptin levels in the gingival crevicular fluid (GCF), saliva and blood serum of patients with periodontal disease compared to healthy individuals. The aim of the present study was to compare the salivary leptin levels in patients with advanced periodontitis and healthy individuals. Materials and Methods: In this case-control study, the salivary samples of healthy individuals and patients with advanced periodontitis with clinical attachment loss >5mm were obtained using a standardized method and the leptin levels were measured in the salivary samples by means of ELISA. The effects of the periodontal status and sex on the salivary leptin levels of both groups were statistically analyzed by two-way ANOVA. Results: The means ± standard deviation (SD) of salivary leptin levels in healthy subjects and patients with advanced periodontitis were 34.27±6.88 and 17.87±5.89 pg/mL, respectively. Statistical analysis showed that the effect of sex on the salivary leptin levels was not significant (P=0.91), while the effect of advanced periodontitis on the salivary leptin levels was significant compared to healthy individuals (P<0.0001). Conclusions: In patients with advanced periodontitis, the salivary leptin levels were significantly lower compared to healthy individuals. Thus, assessment of salivary leptin can be done as a non-invasive and simple method to determine the susceptibility of patients to advanced periodontitis. PMID:27536322

  8. Ancient origins and evolutionary conservation of intracellular and neural signaling pathways engaged by the leptin receptor.

    PubMed

    Cui, Melissa Y; Hu, Caroline K; Pelletier, Chris; Dziuba, Adam; Slupski, Rose H; Li, Choi; Denver, Robert J

    2014-11-01

    In mammals, leptin acts on leptin receptor (LepR) -expressing neurons in the brain to suppress food intake and stimulate whole-body metabolism. A similar action of leptin on food intake has been reported in the frog Xenopus laevis and in several bony fishes. However, the intracellular signaling and neural pathways by which leptin regulates energy balance have not been investigated outside of mammals. Using reporter assays and site-directed mutagenesis we show that the frog LepR signals via signal transducer and activator of transcription (STAT) 3 and STAT5 through evolutionarily conserved tyrosine residues in the LepR cytoplasmic domain. In situ hybridization histochemistry for LepR mRNA in brain and pituitary showed strong expression in the magno- and parvocellular divisions of the anterior preoptic area (homologous to the mammalian paraventricular nucleus), the suprachiasmatic nucleus, ventral hypothalamus, and pars intermedia and pars distalis of the anterior pituitary. Leptin injection increased phosphorylated STAT3 immunoreactivity in LepR mRNA-positive cells, and induced socs3 and pomc mRNAs. Microarray analysis of preoptic area/hypothalamus/pituitary 2 hours after leptin injection identified leptin-regulated genes that included c-fos, a known leptin-activated gene; pituitary follicle-stimulating hormone subunit β, suggesting an important role for leptin in the reproductive axis of frogs; and B-cell translocation factor 2, which has important functions in neurogenesis. Our findings support that the intracellular signaling pathways and neural substrates that mediate leptin actions on energy balance were present in the common ancestor of modern amphibians and amniotes and have been conserved over 350 million years of evolutionary time.

  9. Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats.

    PubMed

    Arnold, Amy C; Diz, Debra I

    2014-12-01

    The decline in cardiovagal baroreflex function that occurs with aging is accompanied by an increase in circulating leptin levels. Our previous studies showed that exogenous leptin impairs the baroreflex sensitivity for control of heart rate in younger rats, but the contribution of this hormone to baroreflex dysfunction during aging is unknown. Thus we assessed the effect of bilateral leptin microinjection (500 fmol/60 nl) within the solitary tract nucleus (NTS) on the baroreflex sensitivity in older (66 ± 2 wk of age) urethane/chloralose anesthetized Sprague-Dawley rats with elevated circulating leptin levels. In contrast to the 63% reduction observed in younger rats, leptin did not alter the baroreflex sensitivity for bradycardia evoked by phenylephrine in older rats (0.76 ± 0.19 baseline vs. 0.71 ± 0.15 ms/mmHg after leptin; P = 0.806). We hypothesized that this loss of sensitivity reflected endogenous suppression of the baroreflex by elevated leptin, rather than cardiovascular resistance to the peptide. Indeed, NTS administration of a leptin receptor antagonist (75 pmol/120 nl) improved the baroreflex sensitivity for bradycardia in older rats (0.73 ± 0.13 baseline vs. 1.19 ± 0.26 at 10 min vs. 1.87 ± 0.32 at 60 min vs. 1.22 ± 0.54 ms/mmHg at 120 min; P = 0.002), with no effect in younger rats. There was no effect of the leptin antagonist on the baroreflex sensitivity for tachycardia, responses to cardiac vagal chemosensitive fiber activation, or resting hemodynamics in older rats. These findings suggest that the actions of endogenous leptin within the NTS, either produced locally or derived from the circulation, contribute to baroreflex suppression during aging. PMID:25260611

  10. Serum leptin as an indicator of fat levels in white-tailed deer (Odocoileus virginianus) in the southeastern USA.

    PubMed

    Chitwood, M Colter; Phillips, Shannon P; Whisnant, Scott; Tyndall, James; Lashley, Marcus A; DePerno, Christopher S

    2014-10-01

    Leptin is a hormone that plays a key role in regulating energy intake, appetite, and metabolism. In some mammals, leptin has been shown to circulate at levels proportional to body fat, which could make it useful for nonlethal evaluation of body condition. Leptin's usefulness for estimating fat levels (i.e., body condition) of white-tailed deer (Odocoileus virginianus) is unknown. We quantified serum leptin concentrations in a sample of free-ranging, female deer collected in July 2008 and March 2009 from coastal North Carolina, USA. We compared leptin concentrations with kidney fat index, femur marrow fat index, and kidney fat mass. Additionally, we assessed differences in leptin concentrations between the two seasons, lactating and nonlactating females, and gestating and nongestating females. Leptin concentrations were similar between seasons but were lower in lactating and gestating females. We did not detect significant relationships between leptin and the body fat metrics, indicating that leptin may have limited value for estimating fat reserves in white-tailed deer.

  11. Effects of estradiol and FSH on leptin levels in women with suppressed pituitary

    PubMed Central

    2012-01-01

    Background Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin. Methods A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student’s t-test and Pearson’s correlation test. Results We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate. Conclusions This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH. PMID:22703959

  12. The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology.

    PubMed

    Sharma, Vijay; McNeill, John H

    2005-04-01

    Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite. More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin increases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin produces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothelium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet aggregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their pathophysiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.

  13. Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma

    PubMed Central

    Oba, Junna; Wei, Wei; Gershenwald, Jeffrey E.; Johnson, Marcella M.; Wyatt, Cynthia M.; Ellerhorst, Julie A.; Grimm, Elizabeth A.

    2016-01-01

    Abstract The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a “raw” (assay value) and an “adjusted” value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients. PMID:26986135

  14. The impact of dietary fat composition on serum leptin concentrations in healthy nonobese men and women.

    PubMed

    Kratz, Mario; von Eckardstein, Arnold; Fobker, Manfred; Buyken, Anette; Posny, Nicole; Schulte, Helmut; Assmann, Gerd; Wahrburg, Ursel

    2002-11-01

    The recently discovered hormone leptin is primarily secreted by adipose tissue and serves as an internal signal indicating the size of body fat stores. The aim of the present study was to investigate the impact of the dietary fatty acid composition on serum leptin concentrations. Therefore, serum leptin levels were measured by RIA in healthy nonobese men (n = 30) and women (n = 25). First, all participants received a baseline high-fat diet, rich in saturated fat, for 2 wk and were then randomly assigned to one of three high-fat dietary treatments, which contained refined olive oil (rich in monounsaturated fatty acids, n = 19), rapeseed oil [rich in monounsaturated fatty acids and alpha-linolenic acid (18:3n-3), n = 17], or sunflower oil (rich in n-6-polyunsaturated fatty acids, n = 19) as the principal source of fat for 4 wk. On the rapeseed oil diet, serum leptin concentrations increased slightly in men [+0.25 ng/ml, T(9) = -2.778, P = 0.021], but decreased distinctly in women [-4.70 ng/ml, T(6) = 5.083, P = 0.002]. Both the olive oil and the sunflower oil diet did not affect serum leptin concentrations. Thus, it is proposed that serum leptin levels were affected by the high amount of alpha-linolenic acid in rapeseed oil. However, questions remain as to why this diet differently affected serum leptin in men and women.

  15. The role of leptin in striped hamsters subjected to food restriction and refeeding

    PubMed Central

    ZHAO, Zhi-Jun; LIU, Yong-An; XING, Jing-Ya; ZHANG, Mao-Lun; NI, Xiao-Ying; CAO, Jing

    2014-01-01

    Food restriction (FR) and refeeding (Re) have been suggested to impair body mass regulation and thereby making it easier to regain the lost weight and develop over-weight when FR ends. However, it is unclear if this is the case in small mammals showing seasonal forging behaviors. In the present study, energy budget, body fat and serum leptin level were measured in striped hamsters that were exposed to FR-Re. The effects of leptin on food intake, body fat and genes expressions of several hypothalamus neuropeptides were determined. Body mass, fat content and serum leptin level decreased during FR and then increased during Re. Leptin supplement significantly attenuated the increase in food intake during Re, decreased genes expressions of neuropepetide Y (NPY) and agouti-related protein (AgRP) of hypothalamus and leptin of white adipose tissue (WAT). Hormone-sensitive lipase (HSL) gene expression of WAT increased in leptin-treated hamsters that were fed ad libitum, but decreased in FR-Re hamsters. This indicates that the adaptive regulation of WAT HSL gene expression may be involved in the mobilization of fat storage during Re, which partly contributes to the resistance to FR-Re-induced overweight. Leptin may be involved in the down regulations of hypothalamus orexigenic peptides gene expression and consequently plays a crucial role in controlling food intake when FR ends. PMID:25017744

  16. Does leptin signal adiposity in the egg-laying mammal, Tachyglossus aculeatus?

    PubMed

    Sprent, Jenny; Jones, Susan M; Nicol, Stewart C

    2012-09-01

    Leptin is a peptide hormone best known for its role in feedback regulation of adiposity in eutherian mammals. Normally an increase in adipose tissue mass leads to an increase in circulating leptin which increases energy expenditure and limits food intake, but in hibernating eutherian mammals this relationship may change to allow prehibernatory fattening. The echidna (Tachyglossus aculeatus) is a monotreme mammal which accumulates significant fat reserves before entering hibernation, and mates immediately at the end of hibernation. We hypothesised that echidnas would show a strong relationship between body mass and plasma leptin for most of the year which would change during the pre-hibernatory period. We measured plasma leptin and body mass in free-ranging echidnas over several reproductive and hibernation cycles. There were significant seasonal variations in plasma leptin in both sexes, with the highest levels occurring in hibernation and in mating females. The lowest levels were found in males when they were foraging maximally after the reproductive period. We used mass%, body mass at the time of sampling as a percentage of long term mean mass, as a proxy for adiposity. There was a weak negative relationship between mass% and plasma leptin, from which we infer a weak negative relationship between adiposity and plasma leptin as has been found in reptiles and birds, rather than the strong positive relationship found in other mammals. PMID:22750512

  17. Regulation of the Na,K-pump by leptin in 3T3-L1 fibroblasts.

    PubMed

    Sweeney, G; Niu, W; Kanani, R; Klip, A

    2000-03-01

    Leptin, the product of the obesity (ob) gene, controls energy intake and expenditure primarily by actions on the central nervous system. However, recently it has become apparent that leptin also elicits a growing and diverse array of effects on peripheral tissues. The Na,K-pump is an electrogenic plasma membrane protein which actively extrudes 3Na+ ions and imports 2K+ ions per molecule of ATP hydrolysed. The pump is responsible for the maintenance of the electrochemical potential of all cells, which in turn drives all ion-coupled transport mechanisms. In this study we use 3T3-L1 fibroblasts to show that leptin inhibits Na,K-pump activity, as assessed by ouabain-sensitive 86Rb+ uptake. Inhibition of the Na,K-pump correlated with increased serine phosphorylation of the catalytic Na,K-pump alpha1 subunit. Upon investigation of leptin-stimulated signalling pathways using specific pharmacological inhibitors, only wortmannin prevented inhibition of the Na,K-pump by leptin. Moreover, leptin stimulated phosphotyrosine-associated PI 3-kinase activity in these cells. In summary, leptin was found to inhibit Na,K-pump activity, likely via PI 3-kinase. We propose that this effect may have wide ranging cardiovascular and metabolic implications and perhaps explain physiological effects of the hormone such as natriuresis.

  18. From observation to experimentation: leptin action in the mediobasal hypothalamus1234

    PubMed Central

    Williams, Kevin W; Scott, Michael M; Elmquist, Joel K

    2009-01-01

    The burgeoning obesity epidemic has fueled the drive to describe, mechanistically, metabolic homeostasis. From the early theories implicating glucose as a principal modulator grew an understanding of a complex array of metabolic signals, sensed by peripheral organs along with specific locations within the central nervous system (CNS). The discovery that leptin, an adipose-derived hormone, acts within the mediobasal hypothalamus to control food intake and energy expenditure ushered in a decade of research that went on to describe not only the specific nuclei and cell type, such as proopiomelanocortin neurons of the arcuate nucleus, that respond to leptin but also the signaling cascades that mediated its effects. This review thus highlights the sites and mechanisms of action of leptin, both in the hypothalamus and in extrahypothalamic sites within the CNS, and shows our current knowledge and direction of future research aimed at understanding the multifunctional role of leptin in maintaining metabolic homeostasis. PMID:19176744

  19. Leptin, a mediator of cardiac damage associated with obesity.

    PubMed

    Martínez-Martínez, E; Jurado-López, R; Cervantes-Escalera, P; Cachofeiro, V; Miana, M

    2014-04-01

    Obesity and excess of adipose tissue are associated with the development of cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia. At the cardiac level, various morphological adaptations in cardiac structure and function occur in obese individuals. Different mechanisms linking obesity to these modifications have been postulated. Adipose tissue and epicardial fat releases a large number of cytokines and bioactive mediators such as leptin. Leptin circulates in proportion to body fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. It participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of leptin and the different isoforms of its receptor in different tissues including the heart. This hormone has distinct effects on the reproductive, cardiovascular, and immune systems; however, its role in the heart could mediate wide physiological effects observed in obese individuals. Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities. It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines. We herein review the current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage. PMID:25389996

  20. The role of cannabinoids and leptin in neurological diseases.

    PubMed

    Agar, E

    2015-12-01

    Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis and epilepsy. Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear. Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides. Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson's and Alzheimer's. Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases. Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders. PMID:25880465

  1. The role of cannabinoids and leptin in neurological diseases.

    PubMed

    Agar, E

    2015-12-01

    Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis and epilepsy. Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear. Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides. Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson's and Alzheimer's. Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases. Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders.

  2. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

    PubMed

    Wasim, Muhammad; Awan, Fazli Rabbi; Najam, Syeda Sadia; Khan, Abdul Rehman; Khan, Haq Nawaz

    2016-10-01

    Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity. PMID:27313173

  3. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

    PubMed

    Wasim, Muhammad; Awan, Fazli Rabbi; Najam, Syeda Sadia; Khan, Abdul Rehman; Khan, Haq Nawaz

    2016-10-01

    Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.

  4. Sam68 Mediates the Activation of Insulin and Leptin Signalling in Breast Cancer Cells

    PubMed Central

    Pérez-Pérez, Antonio; Sánchez-Jiménez, Flora; Vilariño-García, Teresa; de la Cruz, Luis; Virizuela, Juan A.; Sánchez-Margalet, Víctor

    2016-01-01

    Obesity is a well-known risk factor for breast cancer development in postmenopausal women. High insulin and leptin levels seem to have a role modulating the growth of these tumours. Sam68 is an RNA-binding protein with signalling functions that has been found to be overexpressed in breast cancer. Moreover, Sam68 may be recruited to insulin and leptin signalling pathways, mediating its effects on survival, growth and proliferation in different cellular types. We aimed to study the expression of Sam68 and its phosphorylation level upon insulin and leptin stimulation, and the role of Sam68 in the proliferative effect and signalling pathways that are activated by insulin or leptin in human breast adenocarcinoma cells. In the human breast adenocarcinoma cell lines MCF7, MDA-MB-231 and BT-474, Sam68 protein quantity and gene expression were increased upon leptin or insulin stimulation, as it was checked by qPCR and immunoblot. Moreover, both insulin and leptin stimulation promoted an increase in Sam68 tyrosine phosphorylation and negatively regulated its RNA binding capacity. siRNA was used to downregulate Sam68 expression, which resulted in lower proliferative effects of both insulin and leptin, as well as a lower activation of MAPK and PI3K pathways promoted by both hormones. These effects may be partly explained by the decrease in IRS-1 expression by down-regulation of Sam68. These results suggest the participation of Sam68 in both leptin and insulin receptor signaling in human breast cancer cells, mediating the trophic effects of these hormones in proliferation and cellular growth. PMID:27415018

  5. Leptin activates cytosolic calcium responses through protein kinase-C dependent mechanism in immortalized RFamide-related peptide-3 neurons.

    PubMed

    Ozcan, Mete; Saatci, Tugrul; Ayar, Ahmet; Canpolat, Sinan; Kelestimur, Haluk

    2015-03-19

    RFamide-related peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), seems to be an important regulator of the hypothalamus-pituitary-gonadal (HPG) reproductive axis. Leptin, a permissive hormonal regulator of fertility, provides energy signal to brain. According to current view, leptin does not act directly on gonadotrophin-releasing hormone (GnRH) neurons. RFRP-3 neurons have been shown to express leptin receptors. The goal of the present study was to examine whether leptin acts through RFRP-3 neurons to modulate activity of the GnRH neurons. For this aim, the effects of leptin on intracellular free Ca(2+) levels ([Ca(2+)]i) in RFRP-3 neurons were investigated by using in vitro calcium imaging system. In the present study, rHypoE-7 cell line was used as a model to explore the effects of leptin on RFRP-3 neurons. rHypoE-7 cells were placed on glass coverslip and loaded with 1 μM Fura-2 AM. [Ca(2+)]i responses were quantified by the changes in 340/380 ratio. Leptin (0.1-10 μM) caused increases in [Ca(2+)]i in a dose-dependent manner. The changes in [Ca(2+)]i were significantly attenuated by pre-treatment with protein kinase C inhibitor. These results demonstrate that leptin activates intracellular calcium signaling in RFRP-3 neurons through PKC-dependent pathway, and thus leptin may exert its effect on GnRH neurons by means of RFRP-3 cells.

  6. Relationship between Serum Leptin, Ghrelin and Dietary Macronutrients in Women with Polycystic Ovary Syndrome

    PubMed Central

    Pourghassem Gargari, Bahram; Houjeghani, Shiva; Farzadi, Laya; Houjeghani, Sheyda; Safaeiyan, Abdolrasoul

    2015-01-01

    Background Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. It may involve an impairment in physiologic regulation of leptin and ghrelin. There is limited, controversial data on the relation of dietary components with leptin and ghrelin in PCOS, so the current study has been conducted to explore the effects of different macronutrients on serum levels of leptin and ghrelin in PCOS and healthy subjects. Materials and Methods In this case-control study, we randomly choose 30 PCOS pa- tients and 30 healthy age and body mass index (BMI) matched controls. Intake of macronutrients [protein, total fat, saturated, monounsaturated and polyunsaturated fatty acids (PUFA), carbohydrate, dietary fiber] and energy were assessed using 3-day, 24-hour food recall and food frequency questionnaires (FFQ). Fasting hormonal status was measured for each participant. Results PCOS women had higher levels of serum leptin, insulin, testosterone, and luteinizing hormone (LH), whereas sex hormone-binding globulin (SHBG) was lower compared to healthy women. There was no significant difference in mean ghrelin concentrations between the groups. Among PCOS women, independent of BMI and total energy intake, we observed an inverse association between leptin concentration and total dietary fat (β=-0.16, P<0.05) and saturated fatty acid (SFA) intake (β=-0.58, P<0.05). This relationship was not seen in the healthy subjects. There was no significant association between ghrelin and macronutrients in PCOS and healthy participants. Conclusion Certain habitual dietary components such as fat and SFA may decrease serum leptin, whereas ghrelin is not influenced by these in PCOS women. More studies are needed to better clarify the effects of dietary macronutrients on serum leptin and ghrelin. PMID:26644854

  7. Adiponectin, leptin, and yoga practice.

    PubMed

    Kiecolt-Glaser, Janice K; Christian, Lisa M; Andridge, Rebecca; Hwang, Beom Seuk; Malarkey, William B; Belury, Martha A; Emery, Charles F; Glaser, Ronald

    2012-12-01

    To address the mechanisms underlying hatha yoga's potential stress-reduction benefits, we compared adiponectin and leptin data from well-matched novice and expert yoga practitioners. These adipocytokines have counter-regulatory functions in inflammation; leptin plays a proinflammatory role, while adiponectin has anti-inflammatory properties. Fifty healthy women (mean age=41.32, range=30-65), 25 novices and 25 experts, provided fasting blood samples during three separate visits. Leptin was 36% higher among novices compared to experts, P=.008. Analysis of adiponectin revealed a borderline effect of yoga expertise, P=.08; experts' average adiponectin levels were 28% higher than novices across the three visits. In contrast, experts' average adiponectin to leptin ratio was nearly twice that of novices, P=.009. Frequency of self-reported yoga practice showed significant negative relationships with leptin; more weeks of yoga practice over the last year, more lifetime yoga sessions, and more years of yoga practice were all significantly associated with lower leptin, with similar findings for the adiponectin to leptin ratio. Novices and experts did not show even marginal differences on behavioral and physiological dimensions that might represent potential confounds, including BMI, central adiposity, cardiorespiratory fitness, and diet. Prospective studies addressing increased risk for type II diabetes, hypertension, and cardiovascular disease have highlighted the importance of these adipocytokines in modulating inflammation. Although these health risks are clearly related to more extreme values then we found in our healthy sample, our data raise the possibility that longer-term and/or more intensive yoga practice could have beneficial health consequences by altering leptin and adiponectin production. PMID:22306535

  8. Expression of leptin and leptin receptor isoforms in the human stomach

    PubMed Central

    Mix, H; Widjaja, A; Jandl, O; Cornberg, M; Kaul, A; Goke, M; Beil, W; Kuske, M; Brabant, G; Manns, M; Wagner, S

    2000-01-01

    BACKGROUND—Leptin is an important regulator of food intake and energy expenditure. Initially it was thought to be expressed exclusively in and secreted by adipocytes. Recently, leptin expression was also noted in other tissues, including rat gastric mucosa. Information on leptin and leptin receptor expression in the human stomach is lacking.
AIM—To investigate expression of leptin and its corresponding receptors in human gastric epithelial cells.
METHODS—Fundic and antral gastric mucosal biopsies, primary cultures of human gastric epithelial cells, and the human gastric cancer cell line AGS were screened for expression of leptin and different leptin receptor isoform mRNA by reverse transcriptase-polymerase chain reaction. Immunohistochemistry was performed for localisation of leptin and leptin receptor proteins in gastric mucosa.
RESULTS—mRNA of leptin and its four receptor isoforms (huOB-R, long receptor isoform; huB219.1-3, short receptor isoforms) was detected in gastric mucosal biopsies, cultured human gastric epithelial cells, and gastric cancer cells. Immunohistochemistry demonstrated that chief as well as parietal cells were reactive to leptin and leptin receptors.
CONCLUSIONS—Leptin and leptin receptors are expressed in human gastric mucosa. These findings suggest a paracrine and/or autocrine effect of leptin on gastric epithelial cell function.


Keywords: leptin; leptin receptor isoforms; immunohistochemistry; gastric mucosa PMID:10986207

  9. Time-dependent effects of leptin on food intake and locomotor activity in goldfish.

    PubMed

    Vivas, Y; Azpeleta, C; Feliciano, A; Velarde, E; Isorna, E; Delgado, M J; De Pedro, N

    2011-05-01

    The present study investigates the possible circadian dependence of leptin effects on food intake, locomotor activity, glycemia and plasma cortisol levels in goldfish (Carassius auratus). Fish were maintained under 12L:12D photoperiod and subjected to two different feeding schedules, one group fed during photophase (10:00) and the other one during scotophase (22:00). Leptin or saline were intraperitoneally injected at two different times (10:00 or 22:00), coincident or not with the meal time. To eliminate the entraining effect of the light/dark cycle, goldfish maintained under 24h light (LL) were fed and leptin-injected at 10:00. A reduction in food intake and locomotor activity and an increase in glycemia were found in goldfish fed and leptin-injected at 10:00. No significant changes in circulating cortisol were observed. Those effects were not observed when leptin was administered during the scotophase, regardless the feeding schedule; neither in fish maintained under LL, suggesting that a day/night cycle would be necessary to observe the actions of leptin administered during the photophase. Changes in locomotor activity and glycemia were only observed in goldfish when leptin was injected at daytime, coincident with the feeding schedule, suggesting that these leptin actions could be dependent on the feeding time as zeitgeber. In view of these results it appears that the circadian dependence of leptin actions in goldfish can be determined by the combination of both zeitgebers, light/dark cycle and food. Our results point out the relevance of the administration time when investigating regulatory functions of hormones.

  10. Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist.

    PubMed

    Foskolos, A; Ehrhardt, R A; Hileman, S M; Gertler, A; Boisclair, Y R

    2015-11-01

    Ruminants remain productive during the energy insufficiency of late pregnancy or early lactation by evoking metabolic adaptations sparing available energy and nutrients (e.g. higher metabolic efficiency and induction of insulin resistance). A deficit in central leptin signaling triggers these adaptations in rodents but whether it does in ruminants remains unclear. To address this issue, five mature ewes were implanted with intracerebroventricular (ICV) cannula in the third ventricle. They were used in two experiments with an ovine leptin antagonist (OLA) when well-conditioned (average body condition score of 3.7 on a 5 point scale). The first experiment tested the ability of OLA to antagonize leptin under in vivo conditions. Ewes received continuous ICV infusion of artificial cerebrospinal fluid (aCSF), ovine leptin (4 µg/h) or the combination of ovine leptin (4 µg/h) and its mutant version OLA (40 µg/h) for 48 h. Dry matter intake (DMI) was measured every day and blood samples were collected on the last day of infusion. ICV infusion of leptin reduced DMI by 24% (P < 0.05), and this effect was completely abolished by OLA co-infusion. A second experiment tested whether a reduction in endogenous leptin signaling in the brain triggers metabolic adaptations. This involved continuous ICV infusions of aCSF or OLA alone (40 µg/h) for 4 consecutive days. The infusion of OLA did not alter voluntary DMI over the treatment period or on any individual day. OLA did not affect plasma variables indicative of insulin action (glucose, non-esterified fatty acids, insulin and the disposition of plasma glucose during an insulin tolerance test) or plasma cortisol, but tended to reduce plasma triiodothyronine and thyroxine (P < 0.07). Overall, these data show that a reduction of central leptin signaling has little impact on insulin action in well-conditioned mature sheep. They also raise the possibility that reduced central leptin signaling plays a role in controlling thyroid

  11. Growth Restriction, Leptin, and the Programming of Adult Behavior in Mice

    PubMed Central

    Meyer, Lauritz R; Zhu, Vivian; Miller, Alise; Roghair, Robert D

    2014-01-01

    Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4–14, C57BL/6 mice were randomized to daily injections of saline or leptin (80 ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/−6 sec vs 87+/−7 sec for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/−10 sec vs 36+/−5 sec, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective. PMID:25196633

  12. Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin.

    PubMed

    Peters, James H; Simasko, Steven M; Ritter, Robert C

    2006-11-30

    The gut-peptide, cholecystokinin (CCK), reduces food intake by acting at CCK-1 receptors on vagal afferent neurons, whereas the feeding effects of the adipokine hormone, leptin, are associated primarily with its action on receptors (ObRb) in the hypothalamus. Recently, however, ObRb mRNA has been reported in vagal afferent neurons, some of which also express CCK-1 receptor, suggesting that leptin, alone or in cooperation with CCK, might activate vagal afferent neurons, and influence food intake via a vagal route. To evaluate these possibilities we have been examining the cellular and behavioral effects of leptin and CCK on vagal afferent neurons. In cultured vagal afferent neurons leptin and CCK evoked short latency, transient depolarizations, often leading to action potentials, and increases in cytosolic calcium. There was a much higher prevalence of CCK and leptin sensitivity amongst cultured vagal afferent neurons that innervate stomach or duodenum than there was in the overall vagal afferent population. Furthermore, almost all leptin-responsive gastric and duodenal vagal afferents also were sensitive to CCK. Leptin, infused into the upper GI tract arterial supply, reduced meal size, and enhanced satiation evoked by CCK. These results indicate that vagal afferent neurons are activated by leptin, and that this activation is likely to participate in meal termination, perhaps by enhancing vagal sensitivity to CCK. Our findings are consistent with the view that leptin and CCK exert their influence on food intake by accessing multiple neural systems (viscerosensory, motivational, affective and motor) at multiple points along the neuroaxis. PMID:16872644

  13. Growth restriction, leptin, and the programming of adult behavior in mice.

    PubMed

    Meyer, Lauritz R; Zhu, Vivian; Miller, Alise; Roghair, Robert D

    2014-12-15

    Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

  14. Variation in plasma leptin-like immunoreactivity in free-living European starlings (Sturnus vulgaris).

    PubMed

    Kordonowy, Lauren L; McMurtry, John P; Williams, Tony D

    2010-03-01

    Leptin, a protein hormone secreted by fat cells, is best known for its role as an adiposity signal; however, leptin has diverse physiological roles ranging from regulation of feeding behavior and body weight, to effects on reproduction and immune function. Although leptin has been extensively studied in mammals, the identification and function of leptin in birds remains controversial, and studies have focused on captive or domesticated species. Here, we describe changes in plasma leptin-like immunoreactivity during the reproductive and non-reproductive seasons in free-living female European starlings (Sturnus vulgaris). Plasma leptin-like immunoreactivity was high during egg-laying (27.8+/-2.4 ng/mL) and clutch completion (23.8+/-1.6 ng/mL), decreased during incubation (13.0+/-1.6 ng/mL) and chick-rearing (12.0+/-1.3 ng/mL), but was elevated again in non-breeders in November (23.7+/-1.1 ng/mL). Although there was marked and consistent variation in total body mass and body composition with breeding stage and season in this population, plasma leptin-like immunoreactivity did not parallel changes in body mass or body composition. These data suggest that the strong positive relationship between plasma leptin-like immunoreactivity and body mass reported for captive birds and mammals does not hold for free-living birds. Rather, among free-living female European starlings, variation in plasma leptin-like immunoreactivity is associated with breeding stage or seasonal variation per se, and we discuss possible mechanisms underlying this variation, focusing on ovarian function and egg production. PMID:19796643

  15. Leptin deficiency in maltreated children

    PubMed Central

    Danese, A; Dove, R; Belsky, D W; Henchy, J; Williams, B; Ambler, A; Arseneault, L

    2014-01-01

    Consistent with findings from experimental research in nonhuman primates exposed to early-life stress, children exposed to maltreatment are at high risk of detrimental physical health conditions, such as obesity and systemic inflammation. Because leptin is a key molecule involved in the regulation of both energy balance and immunity, we investigated abnormalities in leptin physiology among maltreated children. We measured leptin, body mass index and C-reactive protein in 170 12-year-old children members of the Environmental-Risk Longitudinal Twin Study, for whom we had prospectively-collected information on maltreatment exposure. We found that maltreated children exhibited blunted elevation in leptin levels in relation to increasing levels of physiological stimuli, adiposity and inflammation, compared with a group of non-maltreated children matched for gender, zygosity and socioeconomic status. These findings were also independent of key potential artifacts and confounders, such as time of day at sample collection, history of food insecurity, pubertal maturation and depressive symptoms. Furthermore, using birth weight as a proxy measure for leptin, we found that physiological abnormalities were presumably not present at birth in children who went on to be maltreated but only emerged over the course of childhood, after maltreatment exposure. Leptin deficiency may contribute to onset, persistence and progression of physical health problems in maltreated children. PMID:25247591

  16. Leptin deficiency in maltreated children.

    PubMed

    Danese, A; Dove, R; Belsky, D W; Henchy, J; Williams, B; Ambler, A; Arseneault, L

    2014-01-01

    Consistent with findings from experimental research in nonhuman primates exposed to early-life stress, children exposed to maltreatment are at high risk of detrimental physical health conditions, such as obesity and systemic inflammation. Because leptin is a key molecule involved in the regulation of both energy balance and immunity, we investigated abnormalities in leptin physiology among maltreated children. We measured leptin, body mass index and C-reactive protein in 170 12-year-old children members of the Environmental-Risk Longitudinal Twin Study, for whom we had prospectively-collected information on maltreatment exposure. We found that maltreated children exhibited blunted elevation in leptin levels in relation to increasing levels of physiological stimuli, adiposity and inflammation, compared with a group of non-maltreated children matched for gender, zygosity and socioeconomic status. These findings were also independent of key potential artifacts and confounders, such as time of day at sample collection, history of food insecurity, pubertal maturation and depressive symptoms. Furthermore, using birth weight as a proxy measure for leptin, we found that physiological abnormalities were presumably not present at birth in children who went on to be maltreated but only emerged over the course of childhood, after maltreatment exposure. Leptin deficiency may contribute to onset, persistence and progression of physical health problems in maltreated children. PMID:25247591

  17. Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation.

    PubMed

    Sato, Akinori; Kamekura, Ryuta; Kawata, Koji; Kawada, Masaya; Jitsukawa, Sumito; Yamashita, Keiji; Sato, Noriyuki; Himi, Tetsuo; Ichimiya, Shingo

    2016-01-01

    Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.

  18. Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation

    PubMed Central

    Kawata, Koji; Kawada, Masaya; Jitsukawa, Sumito; Yamashita, Keiji; Sato, Noriyuki; Himi, Tetsuo; Ichimiya, Shingo

    2016-01-01

    Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema. PMID:27366905

  19. Leptin and the Regulation of Renal Sodium Handling and Renal Na-Transporting ATPases: Role in the Pathogenesis of Arterial Hypertension.

    PubMed

    Bełtowski, Jerzy

    2010-02-01

    Leptin, an adipose tissue hormone which regulates food intake, is also involved in the pathogenesis of arterial hypertension. Plasma leptin concentration is increased in obese individuals. Chronic leptin administration or transgenic overexpression increases blood pressure in experimental animals, and some studies indicate that plasma leptin is elevated in hypertensive subjects independently of body weight. Leptin has a dose- and time-dependent effect on urinary sodium excretion. High doses of leptin increase Na(+) excretion in the short run; partially by decreasing renal Na(+),K(+)-ATPase (sodium pump) activity. This effect is mediated by phosphatidylinositol 3-kinase (PI3K) and is impaired in animals with dietary-induced obesity. In contrast to acute, chronic elevation of plasma leptin to the level observed in patients with the metabolic syndrome impairs renal Na(+) excretion, which is associated with the increase in renal Na(+),K(+)-ATPase activity. This effect results from oxidative stress-induced deficiency of nitric oxide and/or transactivation of epidermal growth factor receptor and subsequent stimulation of extracellular signal-regulated kinases. Ameliorating "renal leptin resistance" or reducing leptin level and/or leptin signaling in states of chronic hyperleptinemia may be a novel strategy for the treatment of arterial hypertension associated with the metabolic syndrome.

  20. Mood disorders: A potential link between ghrelin and leptin on human body?

    PubMed Central

    Zarouna, Stalo; Wozniak, Greta; Papachristou, Anastasia Ioannis

    2015-01-01

    Leptin and ghrelin are two hormones associated with multiple physiological functions, especially energy balance. Leptin is an adipocyte-secreted hormone discovered in 1950 and ghrelin which was found in 1999, is a peptide hormone produced and secreted in the stomach. A number of previous studies showed that these hormones could be associated with different types of mood disorders. The results of previous studies, nevertheless, are confounded by diverse sample selection and different methodologies. A search for related articles in the PubMed database was attempted. The search covered studies, reports, reviews and editorials published in the last ten years. Older references served as auxiliary sources for comparison purposes. However, due to the different results of the studies, there is a need for more investigation in order to establish the exact biochemical mechanisms that are responsible for these diseases and ghrelin’s and leptin’s effects on mood. PMID:25992324

  1. IGF-I mediated inhibition of leptin receptor expression in porcine hepatocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study was conducted to elucidate hormonal control of leptin receptor gene expression in primary cultures of porcine hepatocytes. Hepatocytes were isolated from pigs (52 kg) and seeded into collagen-coated T-25 flasks. Monolayer cultures were established in medium containing fetal bovine serum fo...

  2. Changes in leptin and metabolite concentrations over time in finishing beef steers and heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leptin is a hormone produced in adipocytes that is involved in the control of feed intake, growth, and carcass composition. Composite breed cows were bred to working ranch bulls representing Angus, Charolais, Gelbvieh, Limousin, Red Angus, and Simmental breeds to produce calves with a wide range in...

  3. Brief Report: Plasma Leptin Levels Are Elevated in Autism: Association with Early Onset Phenotype?

    ERIC Educational Resources Information Center

    Ashwood, Paul; Kwong, Christina; Hansen, Robin; Hertz-Picciotto, Irva; Croen, Lisa; Krakowiak, Paula; Walker, Wynn; Pessah, Isaac N.; Van de Water, Judy

    2008-01-01

    There is evidence of both immune dysregulation and autoimmune phenomena in children with autism spectrum disorders (ASD). We examined the hormone/cytokine leptin in 70 children diagnosed with autism (including 37 with regression) compared with 99 age-matched controls including 50 typically developing (TD) controls, 26 siblings without autism, and…

  4. Ghrelin and leptin interplay in prevention of testicular damage due to cryptochidism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin, the endogenous ligand to the growth hormone secretagogue receptor (ghsr), is centrally implicated in body weight homeostasis. A novel murine model for ghrelin and its physiologic antagonist, leptin, was developed at this institution. Mice with a deletion of ghsr (ghsr -/-) or a targeted dis...

  5. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer

    PubMed Central

    Lipsey, Crystal C; Harbuzariu, Adriana; Daley-Brown, Danielle; Gonzalez-Perez, Ruben R

    2016-01-01

    Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers. PMID:27019796

  6. Cloning and characterization of leptin in a Perciform fish, the striped bass (Morone saxatilis): control of feeding and regulation by nutritional state.

    PubMed

    Won, Eugene T; Baltzegar, David A; Picha, Matthew E; Borski, Russell J

    2012-08-01

    In mammals, leptin is an anorexigenic peptide hormone that regulates energy homeostasis. It is produced predominantly by white adipose tissue and circulates as an endocrine indicator of energy reserves. Teleost leptin has been characterized in a few fish species, but its regulation is not well understood, particularly in response to nutritional status. In this study, we cloned a putative leptin in striped bass (Morone saxatilis) and report the first characterization of leptin in a Perciforme, the largest and most diverse order of fish. The striped bass leptin coding sequence was 65% homologous with pufferfish, 52% with Atlantic salmon, and 46% with human. PCR showed that leptin mRNA was exclusively expressed in the liver, and not adipose or other tissues. The leptin coding sequence of striped bass and the more widely cultured hybrid striped bass variety (HSB; Morone chrysops, white bass×M. saxatilis) were identical. We then evaluated whether the metabolic status of HSB might alter leptin gene expression. Juvenile HSB were subjected to 3weeks feed deprivation followed by 3weeks of refeeding. Quantitative PCR showed that fasting for 3weeks reduced hepatic leptin mRNA levels relative to fed controls. Leptin mRNA levels then increased upon refeeding, albeit levels were not completely restored to those seen in control fish fed throughout the experiment. Intraperitoneal injection of human leptin suppressed appetite in HSB. In as much as hepatic HSB leptin mRNA is regulated by nutritional state and has a corresponding anorexigenic effect, our results suggest that leptin may play a role in energy homeostasis in these advanced Perciformes. PMID:22569172

  7. The expression of leptin, hypothalamic neuropeptides and UCP1 before, during and after fattening in the Daurian ground squirrel (Spermophilus dauricus).

    PubMed

    Xing, Xin; Yang, Ming; Wang, De-Hua

    2015-06-01

    The Daurian ground squirrel (Spermophilus dauricus) accumulates large amounts of body fat during pre-hibernation fattening. Leptin, an adipose-derived hormone, plays important roles in energy balance and thermogenesis. We predicted that body fat accumulation would lead to the elevation of leptin concentration while its effect on satiety would be suppressed in hypothalamus during fattening. In addition, the uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) would increase and correlated positively with leptin concentration before hibernation. Here, we measured serum leptin concentration and leptin mRNA in white adipose tissue (WAT), hypothalamic neuropeptides involved in energy regulation and UCP1 in BAT before, during and after fattening in squirrels. The fat mass gradually increased during fattening but serum leptin increased mainly in the late phase of fattening, which was consistent with leptin mRNA expression in WAT. During fattening, the mRNA of hypothalamic leptin receptor was up-regulated and correlated positively with serum leptin. Orexigenic neuropeptide Y mRNA increased by 67%; however agouti-related peptide remained unchanged before hibernation. There was no significant change in anorexigenic neuropeptide mRNA. No change in suppressor of cytokine signaling-3 and protein tyrosine phosphatase-1B was detected. UCP1 mRNA expression and protein content in BAT increased significantly after fattening. These changes were independent of environmental conditions and serum leptin concentration. Our results suggest that the dissociation of leptin production and adiposity during fattening may facilitate fat accumulation. No evidence of suppressed leptin signal was found in fattening squirrels. The UCP1 recruitment in post-fattening squirrels could occur without winter-like acclimation and increased leptin.

  8. Cloning and characterization of leptin in a Perciform fish, the striped bass (Morone saxatilis): control of feeding and regulation by nutritional state.

    PubMed

    Won, Eugene T; Baltzegar, David A; Picha, Matthew E; Borski, Russell J

    2012-08-01

    In mammals, leptin is an anorexigenic peptide hormone that regulates energy homeostasis. It is produced predominantly by white adipose tissue and circulates as an endocrine indicator of energy reserves. Teleost leptin has been characterized in a few fish species, but its regulation is not well understood, particularly in response to nutritional status. In this study, we cloned a putative leptin in striped bass (Morone saxatilis) and report the first characterization of leptin in a Perciforme, the largest and most diverse order of fish. The striped bass leptin coding sequence was 65% homologous with pufferfish, 52% with Atlantic salmon, and 46% with human. PCR showed that leptin mRNA was exclusively expressed in the liver, and not adipose or other tissues. The leptin coding sequence of striped bass and the more widely cultured hybrid striped bass variety (HSB; Morone chrysops, white bass×M. saxatilis) were identical. We then evaluated whether the metabolic status of HSB might alter leptin gene expression. Juvenile HSB were subjected to 3weeks feed deprivation followed by 3weeks of refeeding. Quantitative PCR showed that fasting for 3weeks reduced hepatic leptin mRNA levels relative to fed controls. Leptin mRNA levels then increased upon refeeding, albeit levels were not completely restored to those seen in control fish fed throughout the experiment. Intraperitoneal injection of human leptin suppressed appetite in HSB. In as much as hepatic HSB leptin mRNA is regulated by nutritional state and has a corresponding anorexigenic effect, our results suggest that leptin may play a role in energy homeostasis in these advanced Perciformes.

  9. Therapeutic use of recombinant methionyl human leptin.

    PubMed

    Vatier, Camille; Gautier, Jean-François; Vigouroux, Corinne

    2012-10-01

    Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

  10. Association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer

    PubMed Central

    Jin, Jing Hui; Kim, Hyun-Jung; Kim, Chan Young; Kim, Yun Hwan; Ju, Woong

    2016-01-01

    Objective Decreased adiponectin and increased leptin plasma concentrations are believed to be associated with the occurrence and progression of cancers such as endometrial cancer and breast cancer. The aim of this study was to explore the association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer. Methods For patients with ovarian cancer and the control group, adiponectin and leptin levels were measured; anthropometric data were obtained during a chart review. Statistical comparisons between groups were analyzed using the Student's t-test; correlations were confirmed using the Pearson correlation. Results The mean adiponectin and leptin concentrations in patients with ovarian cancer were lower than those of the control group (8.25 vs. 11.44 µg/mL, respectively; P=0.026) (7.09 vs. 15.4 ng/mL, respectively; P=0.001). However, there was no significant difference in adiponectin and leptin levels between early-stage (I/II) and advanced-stage (III/IV) disease (P=0.078). Conclusion Compared with other gynecological cancers, the level of adiponectin and leptin were decreased in ovarian cancer that may have some diagnostic value; additional study to elucidate the function of these two hormones in the development of ovarian carcinogenesis is necessitated. PMID:27462594

  11. Roles of leptin and ghrelin in adipogenesis and lipid metabolism of rainbow trout adipocytes in vitro.

    PubMed

    Salmerón, Cristina; Johansson, Marcus; Asaad, Maryam; Angotzi, Anna R; Rønnestad, Ivar; Stefansson, Sigurd O; Jönsson, Elisabeth; Björnsson, Björn Thrandur; Gutiérrez, Joaquim; Navarro, Isabel; Capilla, Encarnación

    2015-10-01

    Leptin and ghrelin are important regulators of energy homeostasis in mammals, whereas their physiological roles in fish have not been fully elucidated. In the present study, the effects of leptin and ghrelin on adipogenesis, lipolysis and on expression of lipid metabolism-related genes were examined in rainbow trout adipocytes in vitro. Leptin expression and release increased from preadipocytes to mature adipocytes in culture, but did not affect the process of adipogenesis. While ghrelin and its receptor were identified in cultured differentiated adipocytes, ghrelin did not influence either preadipocyte proliferation or differentiation, indicating that it may have other adipose-related roles. Leptin and ghrelin increased lipolysis in mature freshly isolated adipocytes, but mRNA expression of lipolysis markers was not significantly modified. Leptin significantly suppressed the fatty acid transporter-1 expression, suggesting a decrease in fatty acid uptake and storage, but did not affect expression of any of the lipogenesis or β-oxidation genes studied. Ghrelin significantly increased the mRNA levels of lipoprotein lipase, fatty acid synthase and peroxisome proliferator-activated receptor-β, and thus appears to stimulate synthesis of triglycerides as well as their mobilization. Overall, the study indicates that ghrelin, but not leptin seems to be an enhancer of lipid turn-over in adipose tissue of rainbow trout, and this regulation may at least partly be mediated through autocrine/paracrine mechanisms. The mode of action of both hormones needs to be further explored to better understand their roles in regulating adiposity in fish.

  12. Leptin rapidly activates PPARs in C2C12 muscle cells

    SciTech Connect

    Bendinelli, Paola; Piccoletti, Roberta . E-mail: Roberta.Piccoletti@unimi.it; Maroni, Paola

    2005-07-08

    Experimental evidence suggests that leptin operates on the tissues, including skeletal muscle, also by modulating gene expression. Using electrophoretic mobility shift assays, we have shown that physiological doses of leptin promptly increase the binding of C2C12 cell nuclear extracts to peroxisome proliferator-activated receptor (PPAR) response elements in oligonucleotide probes and that all three PPAR isoforms participate in DNA-binding complexes. We pre-treated C2C12 cells with AACOCF{sub 3}, a specific inhibitor of cytosolic phospholipase A{sub 2} (cPLA{sub 2}), an enzyme that supplies ligands to PPARs, and found that it abrogates leptin-induced PPAR DNA-binding activity. Leptin treatment significantly increased cPLA{sub 2} activity, evaluated as the release of [{sup 3}H]arachidonic acid from pre-labelled C2C12 cells, as well as phosphorylation. Further, using MEK1 inhibitor PD-98059 we showed that leptin activates cPLA{sub 2} through ERK induction. These results support a direct effect of leptin on skeletal muscle cells, and suggest that the hormone may modulate muscle transcription also by precocious activation of PPARs through ERK-cPLA{sub 2} pathway.

  13. Leptin receptor signaling in T cells is required for Th17 differentiation

    PubMed Central

    Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

    2015-01-01

    The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (lepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted lepR in T cells. In contrast to pleiotropic immune disorders reported in obese mice with leptin or lepR deficiency, we found that lepR deficiency in CD4+ T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation towards a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the signal transducer and activator of transcription 3 (STAT3) and its downstream targets. This study establishes cell-intrinsic roles for leptin receptor signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. PMID:25917102

  14. The effect of cumulative endurance exercise on leptin and adiponectin and their role as markers to monitor training load.

    PubMed

    Voss, S C; Nikolovski, Z; Bourdon, P C; Alsayrafi, M; Schumacher, Y O

    2016-03-01

    Leptin and adiponectin play an essential role in energy metabolism. Leptin has also been proposed as a marker for monitoring training load. So far, no studies have investigated the variability of these hormones in athletes and how they are regulated during cumulative exercise. This study monitored leptin and adiponectin in 15 endurance athletes twice daily in the days before, during and after a 9-day simulated cycling stage race. Adiponectin significantly increased during the race (p = 0.001) and recovery periods (p = 0.002) when compared to the baseline, while leptin decreased significantly during the race (p < 0.0001) and returned to baseline levels during the recovery period. Intra-individual variability was substantially lower than inter-individual variability for both hormones (leptin 34.1 vs. 53.5%, adiponectin 19% vs. 37.2%). With regards to exercise, this study demonstrated that with sufficient, sustained energy expenditure, leptin concentrations can decrease within the first 24 hours. Under the investigated conditions there also appears to be an optimal leptin concentration which ensures stable energy homeostasis, as there was no significant decrease over the subsequent race days. In healthy endurance athletes the recovery of leptin takes 48-72 hours and may even show a supercompensation-like effect. For adiponectin, significant increases were observed within 5 days of commencing racing, with these elevated values failing to return to baseline levels after 3 days of recovery. Additionally, when using leptin and adiponectin to monitor training loads, establishing individual threshold values improves their sensitivity. PMID:26985130

  15. The effect of cumulative endurance exercise on leptin and adiponectin and their role as markers to monitor training load

    PubMed Central

    Nikolovski, Z; Bourdon, PC; Alsayrafi, M; Schumacher, YO

    2015-01-01

    Leptin and adiponectin play an essential role in energy metabolism. Leptin has also been proposed as a marker for monitoring training load. So far, no studies have investigated the variability of these hormones in athletes and how they are regulated during cumulative exercise. This study monitored leptin and adiponectin in 15 endurance athletes twice daily in the days before, during and after a 9-day simulated cycling stage race. Adiponectin significantly increased during the race (p = 0.001) and recovery periods (p = 0.002) when compared to the baseline, while leptin decreased significantly during the race (p < 0.0001) and returned to baseline levels during the recovery period. Intra-individual variability was substantially lower than inter-individual variability for both hormones (leptin 34.1 vs. 53.5%, adiponectin 19% vs. 37.2%). With regards to exercise, this study demonstrated that with sufficient, sustained energy expenditure, leptin concentrations can decrease within the first 24 hours. Under the investigated conditions there also appears to be an optimal leptin concentration which ensures stable energy homeostasis, as there was no significant decrease over the subsequent race days. In healthy endurance athletes the recovery of leptin takes 48-72 hours and may even show a supercompensation-like effect. For adiponectin, significant increases were observed within 5 days of commencing racing, with these elevated values failing to return to baseline levels after 3 days of recovery. Additionally, when using leptin and adiponectin to monitor training loads, establishing individual threshold values improves their sensitivity. PMID:26985130

  16. Korean Curcuma longa L. induces lipolysis and regulates leptin in adipocyte cells and rats

    PubMed Central

    Song, Won-Yeong

    2016-01-01

    BACKGROUND/OBJECTIVES Turmeric (Curcuma longa L.) has been reported to have many biological functions including anti-obesity. Leptin, peptide hormone produced by adipocytes and its concentration is increased in proportion to the amount of the adipocytes. In the present study, we examined the effects of Korean turmeric on the regulation of adiposity and leptin levels in 3T3-L1 adipocytes and rats fed a high-fat and high-cholesterol diet. MATERIALS/METHODS Leptin secretion, free fatty acid and glycerol contents in 3T3-L1 adipocytes were measured after incubation of cells with turmeric for 24 hours. Rats were divided into four experimental groups: a normal diet group (N), a high-fat and high-cholesterol diet group (HF), a high-fat and high-cholesterol diet group supplemented with 2.5% turmeric extracts (TPA group) and a high-fat and high-cholesterol diet group supplemented with 5% turmeric extracts (TPB group). Serum samples were used for the measurement of leptin concentration. RESULTS Contents of free fatty acid and glycerol showed concentration dependent increase in response to turmeric extracts. Effects of turmeric extracts on reduction of lipid accumulation in 3T3-L1 cells were examined by Oil Red O staining. Treatment with turmeric extracts resulted in increased expression levels of adipose triglyceride lipase and hormone-sensitive lipase mRNA. The concentration of leptin from 3T3-L1 adipocytes was significantly decreased by turmeric. Proportional abdominal and epididymal fats weights of the turmeric 5% supplemented group, TPB has significantly decreased compared to the HF group. The serum levels of leptin in the TPA and TPB groups were significantly lower than those of the HF group. CONCLUSIONS Based on these results, we suggested that Korean turmeric may contribute to the decreasing of body fat and regulating leptin secretion. PMID:27698955

  17. Korean Curcuma longa L. induces lipolysis and regulates leptin in adipocyte cells and rats

    PubMed Central

    Song, Won-Yeong

    2016-01-01

    BACKGROUND/OBJECTIVES Turmeric (Curcuma longa L.) has been reported to have many biological functions including anti-obesity. Leptin, peptide hormone produced by adipocytes and its concentration is increased in proportion to the amount of the adipocytes. In the present study, we examined the effects of Korean turmeric on the regulation of adiposity and leptin levels in 3T3-L1 adipocytes and rats fed a high-fat and high-cholesterol diet. MATERIALS/METHODS Leptin secretion, free fatty acid and glycerol contents in 3T3-L1 adipocytes were measured after incubation of cells with turmeric for 24 hours. Rats were divided into four experimental groups: a normal diet group (N), a high-fat and high-cholesterol diet group (HF), a high-fat and high-cholesterol diet group supplemented with 2.5% turmeric extracts (TPA group) and a high-fat and high-cholesterol diet group supplemented with 5% turmeric extracts (TPB group). Serum samples were used for the measurement of leptin concentration. RESULTS Contents of free fatty acid and glycerol showed concentration dependent increase in response to turmeric extracts. Effects of turmeric extracts on reduction of lipid accumulation in 3T3-L1 cells were examined by Oil Red O staining. Treatment with turmeric extracts resulted in increased expression levels of adipose triglyceride lipase and hormone-sensitive lipase mRNA. The concentration of leptin from 3T3-L1 adipocytes was significantly decreased by turmeric. Proportional abdominal and epididymal fats weights of the turmeric 5% supplemented group, TPB has significantly decreased compared to the HF group. The serum levels of leptin in the TPA and TPB groups were significantly lower than those of the HF group. CONCLUSIONS Based on these results, we suggested that Korean turmeric may contribute to the decreasing of body fat and regulating leptin secretion.

  18. Discovery of a novel functional leptin protein (LEP) in zebra finches: evidence for the existence of an authentic avian leptin gene predominantly expressed in the brain and pituitary.

    PubMed

    Huang, Guian; Li, Juan; Wang, Hongning; Lan, Xinyu; Wang, Yajun

    2014-09-01

    Leptin (LEP) is reported to play important roles in controlling energy balance in vertebrates, including birds. However, it remains an open question whether an authentic "LEP gene" exists and functions in birds. Here, we identified and characterized a LEP gene (zebra finch LEP [zbLEP]) encoding a 172-amino acid precursor in zebra finches. Despite zbLEP showing limited amino acid sequence identity (26%-29%) to human and mouse LEPs, synteny analysis proved that zbLEP is orthologous to mammalian LEP. Using a pAH32 luciferase reporter system and Western blot analysis, we demonstrated that the recombinant zbLEP protein could potently activate finch and chicken LEP receptors (zbLEPR; cLEPR) expressed in human embryonic kidney 293 cells and enhance signal transducer and activator of transcription 3 phosphorylation, further indicating that zbLEP is a functional ligand for avian LEPRs. Interestingly, quantitative real-time RT-PCR revealed that zbLEP mRNA is expressed nearly exclusively in the pituitary and various brain regions but undetectable in adipose tissue and liver, whereas zbLEPR mRNA is widely expressed in adult finch tissues examined with abundant expression noted in pituitary, implying that unlike mammalian LEP, finch LEP may not act as an adipocyte-derived signal to control energy balance. As in finches, a LEP highly homologous to zbLEP was also identified in budgerigar genome. Strikingly, finch and budgerigar LEPs show little homology with chicken LEP (cLEP) previously reported, suggesting that the so-called cLEP is incorrect. Collectively, our data provide convincing evidence for the existence of an authentic functional LEP in avian species and suggest an important role of brain- and pituitary-derived LEP played in vertebrates.

  19. Leptin-induced downregulation of the rat hippocampal somatostatinergic system may potentiate its anorexigenic effects.

    PubMed

    Perianes-Cachero, Arancha; Burgos-Ramos, Emma; Puebla-Jiménez, Lilian; Canelles, Sandra; Viveros, María Paz; Mela, Virginia; Chowen, Julie A; Argente, Jesús; Arilla-Ferreiro, Eduardo; Barrios, Vicente

    2012-12-01

    The learning and memory mechanisms in the hippocampus translate hormonal signals of energy balance into behavioral outcomes involved in the regulation of food intake. As leptin and its receptors are expressed in the hippocampus and somatostatin (SRIF), an orexigenic neuropeptide, may inhibit leptin-mediated suppression of food intake in other brain areas, we asked whether chronic leptin infusion induces changes in the hippocampal somatostatinergic system and whether these modifications are involved in leptin-mediated effects. We studied 18 male Wistar rats divided into three groups: controls (C), treated intracerebroventricularly (icv) with leptin (12 μg/day) for 14 days (L) and a pair-fed group (PF) that received the same amount of food consumed by the L group. Food restriction increased whereas leptin decreased the hippocampal SRIF receptor density, due to changes in SRIF receptor 2 protein levels. These changes in the PF group were concurrent with an increase of hippocampal G protein-coupled receptor kinase 2 protein levels and activation of Akt and cyclic AMP response element binding protein. The inhibitory effect of SRIF on adenylyl cyclase (AC) activity, however, was decreased in L rats, coincident with lower G inhibitory α3 and higher AC-I levels as well as signal transducer and activator of transcription factor 3 activation. In addition, 20 male Wistar rats were included to analyze whether the leptin antagonist L39A/D40A/F41A and the SRIF receptor agonist SMS 201-995 modify SRIF signaling and food intake, respectively. Administration of L39A/D40A/F41A reversed changes in SRIF signaling, whereas SMS 201-995 ameliorated food consumption in L. Altogether, these results suggest that increased somatostatinergic tone in PF rats may be a mechanism to improve the hippocampal orexigenic effects in a situation of metabolic demand, whereas down-regulation of this system in L rats may represent a mechanism to enhance the anorexigenic effects of leptin.

  20. Exploring the structure and conformational landscape of human leptin. A molecular dynamics approach.

    PubMed

    Chimal-Vega, Brenda; Paniagua-Castro, Norma; Carrillo Vazquez, Jonathan; Rosas-Trigueros, Jorge L; Zamorano-Carrillo, Absalom; Benítez-Cardoza, Claudia G

    2015-11-21

    Leptin is a hormone that regulates energy homeostasis, inflammation, hematopoiesis and immune response, among other functions (Houseknecht et al., 1998; Zhang et al., 1995; Paz-Filho et al., 2010). To obtain its crystallographic structure, it was necessary to substitute a tryptophan for a glutamic acid at position 100, thus creating a mutant leptin that has been reported to have biological activity comparable to the activity of the wild type but that crystallizes more readily. Here, we report a comparative study of the conformational space of WT and W100E leptin using molecular dynamics simulations performed at 300, 400, and 500 K. We detected differences between the interactions of the two proteins with local and distal effects, resulting in changes in the conformation, accessible surface area, compactness, electrostatic potential and dynamic behavior. Additionally, the series of unfolding events that occur when leptin is subjected to high temperature differs for the two constructs. We observed that both proteins are mostly unstructured after 20 ns of MD simulation at 500 K. However, WT leptin maintains a significant amount of secondary structure in helix α2, while the most stable region of W100E leptin is helix α3. Furthermore, we found that the region between residues 25 and 42 might adopt interconverting secondary structures ranging from α-helices and random coils to β-strand structures. Thus, this region can be considered an intrinsically disordered region. This atomistic description supports our understanding of leptin signaling and consequently might facilitate the use of leptin in treatments for the pathophysiologies in which it is implicated.

  1. Leptin increases prostate cancer aggressiveness.

    PubMed

    López Fontana, Constanza M; Maselli, María E; Pérez Elizalde, Rafael F; Di Milta Mónaco, Nicolás A; Uvilla Recupero, Ana L; López Laur, José D

    2011-12-01

    Recent studies indicate that adipose tissue and adipocytokines might affect the development of prostate cancer (PCa). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of this study was to determine the relation between body composition, leptin, and adiponectin levels with the prevalence and aggressiveness of PCa in men of Mendoza, Argentina. Seventy volunteers between 50 and 80 years (35 healthy men as control group and 35 with PCa) were selected. The PCa group was subclassified according to the Gleason Score (GS). Digital rectal examination, transrectal ultrasound, and prostatic biopsy were performed; PSA, testosterone, leptin, and adiponectin levels were determined; and a nutritional interview including anthropometric measurements and a food frequency questionnaire was carried out. Statistical analysis was performed by Student t test, ANOVA I, and Bonferroni (p < 0.05). Body mass index and percentage of body fat mass were not statistically different between PCa and control groups. However, body fat mass was higher in subjects with more aggressive tumors (p = 0.032). No differences were observed regarding leptin levels between the groups. Nevertheless, leptin levels were higher in subjects with high GS (p < 0.001). Adiponectin levels showed no statistical differences regarding the presence and aggressiveness of the tumor (p = 0.131). Finally, consumption and nutrient intake did not differ in the studied groups. In conclusion, body composition and leptin are related to the PCa aggressiveness but not with its prevalence.

  2. Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

    PubMed Central

    van der Plasse, G; van Zessen, R; Luijendijk, M C M; Erkan, H; Stuber, G D; Ramakers, G M J; Adan, R A H

    2015-01-01

    Background/objectives: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. Subjects/methods: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. Results: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). Conclusions: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling. PMID:26183405

  3. Stimulation of leptin secretion by insulin

    PubMed Central

    Tsai, Minglun; Asakawa, Akihiro; Amitani, Haruka; Inui, Akio

    2012-01-01

    Leptin has a crucial role in regulating food intake and maintaining metabolic homeostasis. Although little is known about the process of leptin secretion, insulin, which has an important role in the metabolism of glucose and lipids, is believed to regulate leptin secretion through a posttranscriptional mechanism in the short term, and via glucose metabolism in the long term. The gastric mucosa secretes leptin, but this mechanism has not been completely elucidated. Understanding the mechanism of insulin-regulated leptin secretion could lead to the development of new treatment methods for obesity and its comorbidities, which are serious public health concerns. PMID:23565488

  4. Expression of leptin and its receptor genes in the ovarian follicles of cycling and early pregnant pigs.

    PubMed

    Smolinska, N; Kaminski, T; Siawrys, G; Przala, J

    2013-01-01

    Leptin is a polypeptide hormone produced primarily by adipocytes. It has been implicated in the regulation of satiety and energy homeostasis. Leptin has been suggested to play a role in reproduction based on its involvement in the regulation of the hypothalamic-pituitary-gonadal axis via endocrine, paracrine and/or autocrine pathways. The aim of the present study was to localize the cellular distribution of leptin and the long isoform of leptin receptor (OB-Rb) genes in porcine ovarian antral follicles and to compare the expression levels of leptin and OB-Rb mRNAs in porcine granulosa cells (GC), theca interna (TIC) and theca externa (TEC) cells during the luteal phase of the estrous cycle and in early pregnancy. The expression of leptin and OB-Rb genes was detected in GC, TIC and TEC. Significantly higher levels of leptin gene expression in GC were observed during the mid- and late-luteal phases of the cycle than on days 30 to 32 of pregnancy. On days 14 to 16 of pregnancy, leptin mRNA expression was higher than that on days 14 to 16 of the cycle. The expression of the OB-Rb gene in GC and TEC increased during pregnancy in comparison with the analyzed luteal phases of the cycle. Our results validate the hypothesis that locally produced leptin plays a role in the regulation of porcine reproduction at the ovarian level and exerts a direct effect on porcine follicles. The differences in OB-Rb gene expression in porcine GC and theca cells also suggest that their sensitivity to leptin varies in the ovaries of pregnant and cyclic pigs.

  5. A role for leptin in the antiaging action of dietary restriction: a hypothesis.

    PubMed

    Shimokawa, I; Higami, Y

    1999-12-01

    A neuroendocrine signal may play an important role in the antiaging action of dietary restriction (DR). Recent studies have suggested that falling leptin levels by starvation activate the hypothalamic-pituitary-adrenal axis, and suppress gonadal, somatotropic, and thyroid axes as a response for adaptation. Accumulated evidence indicates that similar hormonal changes also occur in DR rodents. In this article, we advance that a reduction in plasma leptin levels in DR rodents might be a critical neuroendocrine modulator in the antiaging action of dietary restriction.

  6. Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant?

    PubMed

    Alves, Marco G; Jesus, Tito T; Sousa, Mário; Goldberg, Erwin; Silva, Branca M; Oliveira, Pedro F

    2016-01-01

    Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual's nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face.

  7. Leptin promoter variant G2548A is associated with serum leptin and HDL-C levels in a case control observational study in association with obesity in a Pakistani cohort.

    PubMed

    Shabana, -; Hasnain, Shahida

    2016-06-01

    Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the relationship of such a promoter variant of the leptin gene, G-2548A polymorphism, with obesity and its effect on various anthropometric and metabolic parameters in a Pakistani cohort consisting of 250 obese and 225 non-obese control subjects. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the LEP G-2548A polymorphism showed significant association with obesity in Pakistan. In addition, the polymorphism showed association with weight, height, BMI, WC, HDLC and serum leptin levels. The findings suggest that the leptin promoter G-2548A variant may play its part in the progression to obesity by not only affecting the body's fat distribution but also by changing the serum leptin and HDLC levels. PMID:27240985

  8. Mismatch Amplification Mutation Assay Real-Time PCR Analysis of the Leptin Gene G2548A and A19G Polymorphisms and Serum Leptin in Infancy: A Preliminary Investigation.

    PubMed

    Savino, Francesco; Rossi, Lorenza; Di Stasio, Liliana; Galliano, Ilaria; Montanari, Paola; Bergallo, Massimiliano

    2016-01-01

    Leptin is a hormone that regulates food intake and energy metabolism. Its coding gene (LEP) is one of the most promising candidates for obesity. Although some studies have detected associations of different single nucleotide polymorphisms (SNPs) in the LEP gene with serum leptin levels and obesity-related traits, the results are still conflicting. We investigated two SNPs to find relationships with leptin concentrations. Thirty healthy Caucasian infants younger than 6 months were genotyped for the SNPs G2548A and A19G with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system-mismatch amplification mutation assay (ARMS- MAMA) real-time PCR, and serum leptin concentrations were measured with a radioimmunoassay method. Considering the significant linkage disequilibrium observed between the two SNPs, we divided the sample according to the number of GG haplotypes and observed that individuals homozygous for the GG haplotype had higher serum leptin levels in early infancy than the others. Although these preliminary results are based on a limited sample, they suggest that the genetic background seems to play a role in modulating leptin levels in infancy, but changes in leptin levels over infancy and their correlation with obesity need to be further explored. We describe an ARMS-MAMA real-time PCR procedure which could be profitably applied in routine genetic screening.

  9. Hormone levels

    MedlinePlus

    Blood or urine tests can determine the levels of various hormones in the body. This includes reproductive hormones, thyroid hormones, adrenal hormones, pituitary hormones, and many others. For more information, see: ...

  10. Serum leptin and cortisol, related to acutely perceived academic examination stress and performance in female university students.

    PubMed

    Haleem, Darakhshan J; Inam, Qurrat-Ul-Aen; Haider, Saida; Perveen, Tahira; Haleem, Muhammad Abdul

    2015-12-01

    Leptin, identified as an antiobesity hormone, also has important role in responses to stress and processing of memory. This study was designed to determine effects of academic examination stress-induced changes in serum leptin and its impact on academic performance. Eighty five healthy female students (age 19-21 years; BMI 21.9 ± 1.6) were recruited for the study. Serum leptin and cortisol were monitored at base line (beginning of academic session) and on the day of examination; using a standardized ELISA kit. Acute perception of academic examination stress was determined with the help of a questionnaire derived from Hamilton Anxiety Scale and self report of stress perception. Academic performance was evaluated by the percentage of marks obtained in the examination. Serum cortisol levels were positively correlated (p < 0.01) with the subjective perception of examination stress but not with academic performance. There was an inverted U-shape relationship between level of stress and academic performance. Leptin increased in all stress groups and correlated (p < 0.01) positively with academic performance. There was an inverted U-shape relationship between level of stress and circulating leptin. The findings suggest the peptide hormone, leptin, is a biomarker of stress perception and a mediator of facilitating effects of stress on cognition.

  11. Serum leptin and cortisol, related to acutely perceived academic examination stress and performance in female university students.

    PubMed

    Haleem, Darakhshan J; Inam, Qurrat-Ul-Aen; Haider, Saida; Perveen, Tahira; Haleem, Muhammad Abdul

    2015-12-01

    Leptin, identified as an antiobesity hormone, also has important role in responses to stress and processing of memory. This study was designed to determine effects of academic examination stress-induced changes in serum leptin and its impact on academic performance. Eighty five healthy female students (age 19-21 years; BMI 21.9 ± 1.6) were recruited for the study. Serum leptin and cortisol were monitored at base line (beginning of academic session) and on the day of examination; using a standardized ELISA kit. Acute perception of academic examination stress was determined with the help of a questionnaire derived from Hamilton Anxiety Scale and self report of stress perception. Academic performance was evaluated by the percentage of marks obtained in the examination. Serum cortisol levels were positively correlated (p < 0.01) with the subjective perception of examination stress but not with academic performance. There was an inverted U-shape relationship between level of stress and academic performance. Leptin increased in all stress groups and correlated (p < 0.01) positively with academic performance. There was an inverted U-shape relationship between level of stress and circulating leptin. The findings suggest the peptide hormone, leptin, is a biomarker of stress perception and a mediator of facilitating effects of stress on cognition. PMID:26187200

  12. Influence of exogenous leptin on redox homeostasis in neutrophils and lymphocytes cultured in synovial fluid isolated from patients with rheumatoid arthritis

    PubMed Central

    Gajewska, Joanna; Rzodkiewicz, Przemysław; Wojtecka-Łukasik, Elżbieta

    2016-01-01

    Objectives Leptin is an adipose cells derived hormone that regulates energy homeostasis within the body. Energy metabolism of immune cells influences their activity within numerous pathological states, but the effect of leptin on these cells in unclear. On the one hand, it was observed that leptin induces neutrophils chemotaxis and modulates phagocytosis. On the other hand, neutrophils exposed to leptin did not display detectable Ca2+ ions mobilization or β2-integrin upregulation. In this study, we investigated the effect of leptin on the redox homeostasis in lymphocytes and neutrophils. Material and methods Neutrophils and lymphocytes were isolated by density-gradient centrifugation of blood from healthy volunteers. Cells were cultured with or without leptin (100 ng/ml for lymphocytes and 500 ng/ml for neutrophils) or with or without synovial fluid (85%) for 0–72 h. Culture media were not changed during incubation. Cells were homogenized and homogenate was frozen until laboratory measurements. Redox homeostasis was assessed by the reduced glutathione (GSH) vs. oxidized glutathione (GSSG) ratio and membrane lipid peroxidation evaluation. Results Lymphocytes cultured with leptin and synovial fluid showed a significant increase of the GSSG level. The GSSG/GSH ratio increased by 184 ±37%. In neutrophils incubated in a similar environment, the GSSG/GSH ratio increased by just 21 ±7%, and the effect was observed irrespectively of whether they were exposed to leptin or synovial fluid or both together. Neither leptin nor synovial fluid influenced lipid peroxidation in neutrophils, but in lymphocytes leptin intensified lipid peroxidation. Conclusions Leptin altered the lymphocytes, but not neutrophils redox state. Because firstly neutrophils are anaerobic cells and have just a few mitochondria and secondly lymphocytes have typical aerobic metabolism, the divergence of our data supports the hypothesis that leptin induces oxidative stress by modulation of mitochondria

  13. The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation.

    PubMed

    Sinton, C M; Fitch, T E; Gershenfeld, H K

    1999-09-01

    Leptin (ob protein) is an adipose tissue derived circulating hormone that acts at specific receptors in the hypothalamus to reduce food intake. The protein is also critically involved in energy balance and metabolic status. Here the effect of leptin on sleep architecture in rats was evaluated because food consumption and metabolic status are known to influence sleep. Sprague-Dawley rats were chronically implanted with electrodes for EEG and EMG recording and diurnal sleep parameters were quantified over 9-h periods following leptin administration. Murine recombinant leptin (rMuLep) was administered systemically to rats that either had undergone 18 h of prior food deprivation or had received food ad libitum. In the normally fed rats, leptin significantly decreased the duration of rapid eye movement sleep (REMS) by about 30% and increased the duration of slow wave sleep (SWS) by about 13%, the latter effect reflecting enhanced power in the delta frequency band. These results are consistent with studies that have linked changes in metabolic rate with effects on sleep. Leptin administration has previously been shown to alter neuroendocrine parameters that could have mediated these changes in sleep architecture. Unexpectedly, prior food deprivation negated the effect of leptin on both REMS and SWS, a result that emphasizes the significance of the apparent coupling between sleep parameters and energy status.

  14. Increased Soluble Leptin Receptor Levels in Morbidly Obese Patients With Insulin Resistance and Nonalcoholic Fatty Liver disease

    PubMed Central

    Medici, Valentina; Ali, Mohamed R.; Seo, Suk; Aoki, Christopher A.; Rossaro, Lorenzo; Kim, Kyoungmi; Fuller, Will D.; Vidovszky, Tamas J.; Smith, William; Jiang, Joy X.; Maganti, Kalyani; Havel, Peter J.; Kamboj, Amit; Ramsamooj, Rajendra; Török, Natalie J.

    2016-01-01

    The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may correlate better with the features of metabolic syndrome and with the histological grade and stage of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). We studied a population (n = 104) of morbidly obese patients undergoing bariatric surgery. Data including BMI, type 2 diabetes mellitus, hypertension, and hyperlipidemia were obtained. Plasma fasting leptin and SLR, fasting glucose and insulin were measured, and homeostasis model of assessment insulin resistance (HOMAIR) index and FLI were calculated. All patients had intraoperative liver biopsies. Leptin levels correlated with the BMI. The multiple regression analysis indicated that increasing HOMA and decreasing FLI were predictors of steatosis in the liver (P < 0.0003). SLR levels were positively correlated with the presence of diabetes mellitus and the stage of fibrosis. In conclusion, increased SLR levels in morbidly obese patients with diabetes are correlated with the stage of liver fibrosis, and may reflect progressive liver disease. PMID:20448542

  15. Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease.

    PubMed

    Medici, Valentina; Ali, Mohamed R; Seo, Suk; Aoki, Christopher A; Rossaro, Lorenzo; Kim, Kyoungmi; Fuller, Will D; Vidovszky, Tamas J; Smith, William; Jiang, Joy X; Maganti, Kalyani; Havel, Peter J; Kamboj, Amit; Ramsamooj, Rajendra; Török, Natalie J

    2010-12-01

    The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may correlate better with the features of metabolic syndrome and with the histological grade and stage of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). We studied a population (n = 104) of morbidly obese patients undergoing bariatric surgery. Data including BMI, type 2 diabetes mellitus, hypertension, and hyperlipidemia were obtained. Plasma fasting leptin and SLR, fasting glucose and insulin were measured, and homeostasis model of assessment insulin resistance (HOMA(IR)) index and FLI were calculated. All patients had intraoperative liver biopsies. Leptin levels correlated with the BMI. The multiple regression analysis indicated that increasing HOMA and decreasing FLI were predictors of steatosis in the liver (P < 0.0003). SLR levels were positively correlated with the presence of diabetes mellitus and the stage of fibrosis. In conclusion, increased SLR levels in morbidly obese patients with diabetes are correlated with the stage of liver fibrosis, and may reflect progressive liver disease. PMID:20448542

  16. Leptin Manipulation Reduces Appetite and Causes a Switch in Mating Preference in the Plains Spadefoot Toad (Spea bombifrons)

    PubMed Central

    Garcia, Nicholas W.

    2015-01-01

    Condition- or context-dependent mate choice occurs when females modify their mate preferences depending on their internal or external environment. While the ecological and evolutionary factors that favor the evolution of such plasticity are emerging, relatively little is known of the mechanisms underlying such choice. Here we evaluated whether leptin, a protein hormone involved in the regulation of appetite, might affect the expression of condition-dependent mate choice decisions. To do so, we administered leptin to spadefoot toads, Spea bombifrons, which exhibit condition-dependent mate choice for males of their own species versus congeneric males of S. multiplicata. In particular, poor-condition S. bombifrons are more likely than are good-condition S. bombifrons to prefer S. multiplicata males, but only in environments where hybridization between the two species is beneficial. We found that our leptin treatment reduced appetite in S. bombifrons adults, as was expected from leptin's known effects on appetite. However, although we predicted that leptin would reduce female preferences for heterospecific males, we found the opposite. In particular, our leptin treatment generated a consistent, repeatable preference for heterospecifics in an environment where females generally prefer conspecifics regardless of condition. These results indicate that leptin has the potential to affect female mate choice, but that it might do so in non-intuitive ways. PMID:25919309

  17. Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation.

    PubMed

    Bodosi, B; Gardi, J; Hajdu, I; Szentirmai, E; Obal, F; Krueger, J M

    2004-11-01

    To determine the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, cortical brain temperature (Tcrt), and feeding, we determined these parameters in rats in three experimental conditions: in free-feeding rats with normal diurnal rhythms, in rats with feeding restricted to the 12-h light period (RF), and in rats subjected to 5-h of sleep deprivation (SD) at the beginning of the light cycle. Plasma ghrelin and leptin displayed diurnal rhythms with the ghrelin peak preceding and the leptin peak following the major daily feeding peak in hour 1 after dark onset. RF reversed the diurnal rhythm of these hormones and the rhythm of rapid-eye-movement sleep (REMS) and significantly altered the rhythm of Tcrt. In contrast, the duration and intensity of non-REMS (NREMS) were hardly responsive to RF. SD failed to change leptin concentrations, but it promptly stimulated plasma ghrelin and induced eating. SD elicited biphasic variations in the hypothalamic ghrelin contents. SD increased plasma corticosterone, but corticosterone did not seem to influence either leptin or ghrelin. The results suggest a strong relationship between feeding and the diurnal rhythm of leptin and that feeding also fundamentally modulates the diurnal rhythm of ghrelin. The variations in hypothalamic ghrelin contents might be associated with sleep-wake activity in rats, but, unlike the previous observations in humans, obvious links could not be detected between sleep and the diurnal rhythms of plasma concentrations of either ghrelin or leptin in the rat. PMID:15475503

  18. A leptin derived 30-amino-acid peptide modified pegylated poly-L-lysine dendrigraft for brain targeted gene delivery.

    PubMed

    Liu, Yang; Li, Jianfeng; Shao, Kun; Huang, Rongqin; Ye, Liya; Lou, Jinning; Jiang, Chen

    2010-07-01

    The blood-brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone-leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-L-lysine (DGL) is used as non-viral gene vector in this study. DGL-PEG-Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL-PEG-Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL-PEG-Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood-brain barrier.

  19. Global life-long health benefits of repression of hypothalamic NPY system by central leptin gene therapy.

    PubMed

    Kalra, Satya P

    2007-01-01

    A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic NPY system confers obesity, a cluster of metabolic afflictions and shorter lifespan. A state-of-the-art gene transfer technology using recombinant adeno-associated viral vector to overcome hypothalamic leptin insufficiency was employed in rodent models of obesity, metabolic syndrome and shorter lifespan. Our findings show that life-long tonic repression of NPY system with a stable increase in leptin availability in the hypothalamus prevented the age-related and high fat-diet-induced obesity, hyperinsulinemia and diabetes and extended lifespan. Additional health benefits include increased energy expenditure and normalization of neuroendocrine control on reproduction, and promotion of brain and bone growth. We propose that central leptin gene therapy or novel long-acting leptin mimetics should be tested clinically to decelerate the worldwide epidemic of obesity, diabetes and shortened lifespan.

  20. CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.

    PubMed

    Cardinal, Pierre; André, Caroline; Quarta, Carmelo; Bellocchio, Luigi; Clark, Samantha; Elie, Melissa; Leste-Lasserre, Thierry; Maitre, Marlene; Gonzales, Delphine; Cannich, Astrid; Pagotto, Uberto; Marsicano, Giovanni; Cota, Daniela

    2014-10-01

    Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

  1. Correlation of leptin and soluble leptin receptor levels with anthropometric parameters in mother-newborn pairs

    PubMed Central

    Marino-Ortega, Linda A; Molina-Bello, Adiel; Polanco-García, Julio C; Muñoz-Valle, José F; Salgado-Bernabé, Aralia B; Guzmán-Guzmán, Iris P; Parra-Rojas, Isela

    2015-01-01

    The aim of this study was to investigate if anthropometric parameters are associated with both leptin and soluble leptin receptor (sLEPR) levels in newborns and their mothers. This cross-sectional study was performed in 118 mother-newborn pairs. The venous blood sample of mothers was taken before delivery and immediately after delivery an umbilical cord blood sample was collected. Levels of leptin and sLEPR in maternal and umbilical cord sera were assessed by ELISA. Maternal serum concentration of leptin and sLEPR (6.2 and 25.7 ng/ml, respectively) were higher than in umbilical cord blood (2.4 and 14.2 ng/ml, respectively). However, the newborns and their mothers had higher sLEPR levels than leptin levels. In mothers was observed that leptin levels increase with weight gain in pregnancy and decreased sLEPR levels. Cord leptin levels correlated with neonatal birth weight and length, the body circumferences, placental weight and maternal leptin levels. Cord sLEPR levels correlated with maternal sLEPR and leptin levels. Maternal serum concentration of leptin correlated with pre-pregnancy BMI, weight gain, cord sLEPR and leptin levels. Maternal sLEPR concentration correlated with cord sLEPR levels. The leptin and sLEPR levels in mother-newborn pairs are related with anthropometric parameters and an inverse correlation between leptin levels and sLEPR was observed in pairs. PMID:26379933

  2. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta.

    PubMed

    Hoggard, N; Hunter, L; Duncan, J S; Williams, L M; Trayhurn, P; Mercer, J G

    1997-09-30

    Leptin is a 167-aa protein that is secreted from adipose tissue and is important in the regulation of energy balance. It also functions in hematopoiesis and reproduction. To assess whether leptin is involved in fetal growth and development we have examined the distribution of mRNAs encoding leptin and the leptin receptor (which has at least six splice variants) in the 14.5-day postcoitus mouse fetus and in the placenta using reverse transcription-PCR and in situ hybridization. High levels of gene expression for leptin, the leptin receptor, and the long splice variant of the leptin receptor with an intracellular signaling domain were observed in the placenta, fetal cartilage/bone, and hair follicles. Receptor expression also was detected in the lung, as well as the leptomeninges and choroid plexus of the fetal brain. Western blotting and immunocytochemistry, using specific antibodies, demonstrated the presence of leptin and leptin receptor protein in these tissues. These results suggest that leptin may play a role in the growth and development of the fetus, both through placental and fetal expression of the leptin and leptin receptor genes. In the fetus, leptin may be multifunctional and have both paracrine and endocrine effects.

  3. Leptin applications in 2015: What have we learned about leptin and obesity?

    PubMed Central

    Farr, Olivia M.; Gavrieli, Anna; Mantzoros, Christos S.

    2015-01-01

    Purpose of review To summarize previous and current advancements for leptin therapeutics, we described how leptin may be useful in leptin deficient states such as lipodystrophy, for which leptin was recently approved, and how it may be useful in the future for typical obesity. Recent findings The discovery of leptin in 1994 built the foundation for understanding the pathophysiology and treatment of obesity. Leptin therapy reverses morbid obesity related to congenital leptin deficiency and appears to effectively treat lipodystrophy, a finding which has led to the approval of leptin for the treatment of lipodystrophy in the USA and Japan. Typical obesity, on the other hand, is characterized by hyperleptinemia and leptin resistance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but may be useful in combination with other therapies or for weight loss maintenance. Summary Leptin is not yet able to treat typical obesity, however, it is effective for reversing leptin deficiency-induced obesity and lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, while the development of new techniques and drug combinations which may improve leptin’s efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity. PMID:26313897

  4. Modulation of leptin resistance by food compounds.

    PubMed

    Aragonès, Gerard; Ardid-Ruiz, Andrea; Ibars, Maria; Suárez, Manuel; Bladé, Cinta

    2016-08-01

    Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound. PMID:26842874

  5. Role of leptin receptors in granulosa cells during ovulation.

    PubMed

    Dupuis, Lisa; Schuermann, Yasmin; Cohen, Tamara; Siddappa, Dayananda; Kalaiselvanraja, Anitha; Pansera, Melissa; Bordignon, Vilceu; Duggavathi, Raj

    2014-02-01

    Leptin is an important hormone influencing reproductive function. However, the mechanisms underpinning the role of leptin in the regulation of reproduction remain to be completely deciphered. In this study, our objective is to understand the mechanisms regulating the expression of leptin receptor (Lepr) and its role in ovarian granulosa cells during ovulation. First, granulosa cells were collected from superovulated mice to profile mRNA expression of Lepr isoforms (LeprA and LeprB) throughout follicular development. Expression of LeprA and LeprB was dramatically induced in the granulosa cells of ovulating follicles at 4 h after human chorionic gonadotropin (hCG) treatment. Relative abundance of both mRNA and protein of CCAAT/enhancer-binding protein β (Cebpβ) increased in granulosa cells from 1 to 7 h post-hCG. Furthermore, chromatin immunoprecipitation assay confirmed the recruitment of Cebpβ to Lepr promoter. Thus, hCG-induced transcription of Lepr appears to be regulated by Cebpβ, which led us to hypothesise that Lepr may play a role during ovulation. To test this hypothesis, we used a recently developed pegylated superactive mouse leptin antagonist (PEG-SMLA) to inhibit Lepr signalling during ovulation. I.p. administration of PEG-SMLA (10 μg/g) to superovulated mice reduced ovulation rate by 65% compared with control treatment. Although the maturation stage of the ovulated oocytes remained unaltered, ovulation genes Ptgs2 and Has2 were downregulated in PEG-SMLA-treated mice compared with control mice. These results demonstrate that Lepr is dramatically induced in the granulosa cells of ovulating follicles and this induction of Lepr expression requires the transcription factor Cebpβ. Lepr plays a critical role in the process of ovulation by regulating, at least in part, the expression of the important genes involved in the preovulatory maturation of follicles. PMID:24256641

  6. Dynamic changes in leptin distribution in the progression from ovum to blastocyst of the pre-implantation mouse embryo.

    PubMed

    Schulz, Laura C; Roberts, R Michael

    2011-06-01

    The hormone leptin, which is primarily produced by adipose tissue, is a critical permissive factor for multiple reproductive events in the mouse, including implantation. In the CD1 strain, maternally derived leptin from the oocyte becomes differentially distributed among the blastomeres of pre-implantation embryos to create a polarized pattern, a feature consistent with a model of development in which blastomeres are biased toward a particular fate as early as the two-cell stage. In this study, we have confirmed that embryonic leptin is of maternal origin and re-examined leptin distribution in two distinct strains in which embryos were derived after either normal ovulation or superovulation. A polarized pattern of leptin distribution was found in the majority of both CD1 and CF1 embryos (79.1 and 76.9% respectively) collected following superovulation but was reduced, particularly in CF1 embryos (29.8%; P<0.0001), after natural ovulation. The difference in leptin asymmetries in the CF1 strain arose between ovulation and the first cleavage division and was not affected by removal of the zona pellucida. The presence or absence of leptin polarization was not linked to differences in the ability of embryos to normally develop to blastocyst. In the early blastocyst, leptin was confined subcortically to trophectoderm, but on blastocoel expansion, it was lost from the cells. Throughout development, leptin co-localized with LRP2, a multi-ligand transport protein, and its patterning resembled that noted for the maternal-effect proteins OOEP, NLRP5, and PADI6, suggesting that it is a component of the subcortical maternal complex with as yet unknown significance in pre-implantation development.

  7. Leptin modulates the expression of its receptors in the hypothalamic-pituitary-ovarian axis in a differential way.

    PubMed

    Di Yorio, M P; Bilbao, M G; Pustovrh, M C; Prestifilippo, J P; Faletti, A G

    2008-08-01

    To investigate the expression of leptin receptors (Ob-R) in the rat hypothalamus-pituitary-ovarian axis, immature rats were treated with eCG/hCG and Ob-R expression was evaluated by western blot analysis. The Ob-R expression increased 24 h after eCG administration in all the tissues assayed. In the hypothalamus, these levels immediately decreased to those obtained without treatment. In the pituitary, the Ob-R expression continued to be elevated 48 h after eCG administration, whereas the hCG injection did not modify these levels. Similar results were obtained with the ovarian long isoform. To assess the effect of leptin on its receptors, Ob-R was assessed in hypothalamus, pituitary and ovarian explants cultured in the presence or absence of leptin (0.3-500 ng/ml). In the hypothalamus, we found a biphasic effect: the Ob-R expression was either reduced or increased at low or high concentrations of leptin respectively. LH-releasing hormone secretion increased at 1 ng/ml. In the pituitary, Ob-R increased at 10 or 30 ng/ml of leptin for the long and short isoforms respectively. Leptin also induced an increase in LH release at 30 ng/ml. In the ovarian culture, the presence of leptin produced an increase in Ob-R expression at different ranges of concentrations and a dose-dependent biphasic effect on the progesterone production. In conclusion, all these results clearly suggest that leptin is able to modulate the expression of its own receptors in the reproductive axis in a differential way. Moreover, the positive or negative effect that leptin exerts on the ovulatory process may be dependent on this regulation.

  8. Polymorphisms of leptin-b gene associated with growth traits in orange-spotted grouper (Epinephelus coioides).

    PubMed

    Huang, Hai; Wei, Yun; Meng, Zining; Zhang, Yong; Liu, Xiaochun; Guo, Liang; Luo, Jian; Chen, Guohua; Lin, Haoran

    2014-07-07

    In mammals, leptin has been demonstrated to perform important roles in many physiological activities and to influence development, growth, metabolism and reproduction. However, in fish, its function is still unclear. Duplicate leptin genes, leptin-a and leptin-b, have been identified in the orange-spotted grouper. In the present study, the polymorphisms in the leptin-b gene of the orange-spotted grouper were detected, and the relation between these polymorphisms and 12 growth traits were analyzed. Six polymorphisms (including 3 single nucleotide polymorphisms (c.14G>A, c.93A>G, c.149G>A) in exon 1, 2 SNPs (c.181A>G, c.193G>A) in intron 1, and 1 SNP (c.360C>T) in exon 2) were identified and genotyped from 200 different individuals. The results revealed that the SNP c.149G>A was significantly associated with growth traits, that the heterozygous mutation genotype GA having negative effects on growth traits. However, the other five SNPs (c.14G>A, c.93A>G, c.181A>G, c.193G>A, c.360C>T) did not show significant associations with all the growth traits. Compared with our findings in leptin-a gene, the results suggested that the leptin-a hormone has more important physiological effects in fish bodies than the leptin-b type. Moreover, leptin genes were supposed to be one class of major candidate genes of regulating growth traits in the orange-spotted grouper.

  9. Leptin modulates the expression of its receptors in the hypothalamic-pituitary-ovarian axis in a differential way.

    PubMed

    Di Yorio, M P; Bilbao, M G; Pustovrh, M C; Prestifilippo, J P; Faletti, A G

    2008-08-01

    To investigate the expression of leptin receptors (Ob-R) in the rat hypothalamus-pituitary-ovarian axis, immature rats were treated with eCG/hCG and Ob-R expression was evaluated by western blot analysis. The Ob-R expression increased 24 h after eCG administration in all the tissues assayed. In the hypothalamus, these levels immediately decreased to those obtained without treatment. In the pituitary, the Ob-R expression continued to be elevated 48 h after eCG administration, whereas the hCG injection did not modify these levels. Similar results were obtained with the ovarian long isoform. To assess the effect of leptin on its receptors, Ob-R was assessed in hypothalamus, pituitary and ovarian explants cultured in the presence or absence of leptin (0.3-500 ng/ml). In the hypothalamus, we found a biphasic effect: the Ob-R expression was either reduced or increased at low or high concentrations of leptin respectively. LH-releasing hormone secretion increased at 1 ng/ml. In the pituitary, Ob-R increased at 10 or 30 ng/ml of leptin for the long and short isoforms respectively. Leptin also induced an increase in LH release at 30 ng/ml. In the ovarian culture, the presence of leptin produced an increase in Ob-R expression at different ranges of concentrations and a dose-dependent biphasic effect on the progesterone production. In conclusion, all these results clearly suggest that leptin is able to modulate the expression of its own receptors in the reproductive axis in a differential way. Moreover, the positive or negative effect that leptin exerts on the ovulatory process may be dependent on this regulation. PMID:18515494

  10. Concerted Trafficking Regulation of Kv2.1 and KATP Channels by Leptin in Pancreatic β-Cells.

    PubMed

    Wu, Yi; Shyng, Show-Ling; Chen, Pei-Chun

    2015-12-11

    In pancreatic β-cells, voltage-gated potassium 2.1 (Kv2.1) channels are the dominant delayed rectifier potassium channels responsible for action potential repolarization. Here, we report that leptin, a hormone secreted by adipocytes known to inhibit insulin secretion, causes a transient increase in surface expression of Kv2.1 channels in rodent and human β-cells. The effect of leptin on Kv2.1 surface expression is mediated by the AMP-activated protein kinase (AMPK). Activation of AMPK mimics whereas inhibition of AMPK occludes the effect of leptin. Inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase β, a known upstream kinase of AMPK, also blocks the effect of leptin. In addition, the cAMP-dependent protein kinase (PKA) is involved in Kv2.1 channel trafficking regulation. Inhibition of PKA prevents leptin or AMPK activators from increasing Kv2.1 channel density, whereas stimulation of PKA is sufficient to promote Kv2.1 channel surface expression. The increased Kv2.1 surface expression by leptin is dependent on actin depolymerization, and pharmacologically induced actin depolymerization is sufficient to enhance Kv2.1 surface expression. The signaling and cellular mechanisms underlying Kv2.1 channel trafficking regulation by leptin mirror those reported recently for ATP-sensitive potassium (KATP) channels, which are critical for coupling glucose stimulation with membrane depolarization. We show that the leptin-induced increase in surface KATP channels results in more hyperpolarized membrane potentials than control cells at stimulating glucose concentrations, and the increase in Kv2.1 channels leads to a more rapid repolarization of membrane potential in cells firing action potentials. This study supports a model in which leptin exerts concerted trafficking regulation of KATP and Kv2.1 channels to coordinately inhibit insulin secretion.

  11. Leptin regulates energy intake but fails to facilitate hibernation in fattening Daurian ground squirrels (Spermophilus dauricus).

    PubMed

    Xing, Xin; Tang, Gang-Bin; Sun, Ming-Yue; Yu, Chao; Song, Shi-Yi; Liu, Xin-Yu; Yang, Ming; Wang, De-Hua

    2016-04-01

    Body fat storage before hibernation affects the timing of immergence in Daurian ground squirrels (Spermophilus dauricus). Leptin is an adipose signal and plays vital role in energy homeostasis mainly by action in brain. To test the hypothesis that leptin plays a role in facilitating the process of hibernation, squirrels were administrated with recombinant murine leptin (1μg/day) through intracerebroventricular (ICV) injection for 12 days during fattening. From day 7 to 12, animals were moved into a cold room (5±1°C) with constant darkness which functioned as hibernaculum. Energy intake, body mass and core body temperature (Tb) were continuously monitored throughout the course of experiment. Resting metabolic rate (RMR) was measured under both warm and cold conditions. At the end of leptin administration, we measured the serum concentration of hormones related to energy regulation, mRNA expression of hypothalamic neuropeptides and uncoupling protein 1 (UCP1) levels in brown adipose tissue (BAT). Our results showed that during leptin administration, the cumulative food intake and increase of body mass were suppressed while Tb and RMR were unaltered. The proportion of torpid squirrels was not different between two groups. At the end of leptin administration, the expressions of hypothalamic neuropeptide Y and agouti gene-related protein were suppressed. There were no differences in UCP1 mRNA expression or protein content in BAT between groups. Our data suggest that leptin can affect energy intake via hypothalamic neuropeptides, but is not involved in the initiation of hibernation in fattening Daurian ground squirrels.

  12. Leptin regulates energy intake but fails to facilitate hibernation in fattening Daurian ground squirrels (Spermophilus dauricus).

    PubMed

    Xing, Xin; Tang, Gang-Bin; Sun, Ming-Yue; Yu, Chao; Song, Shi-Yi; Liu, Xin-Yu; Yang, Ming; Wang, De-Hua

    2016-04-01

    Body fat storage before hibernation affects the timing of immergence in Daurian ground squirrels (Spermophilus dauricus). Leptin is an adipose signal and plays vital role in energy homeostasis mainly by action in brain. To test the hypothesis that leptin plays a role in facilitating the process of hibernation, squirrels were administrated with recombinant murine leptin (1μg/day) through intracerebroventricular (ICV) injection for 12 days during fattening. From day 7 to 12, animals were moved into a cold room (5±1°C) with constant darkness which functioned as hibernaculum. Energy intake, body mass and core body temperature (Tb) were continuously monitored throughout the course of experiment. Resting metabolic rate (RMR) was measured under both warm and cold conditions. At the end of leptin administration, we measured the serum concentration of hormones related to energy regulation, mRNA expression of hypothalamic neuropeptides and uncoupling protein 1 (UCP1) levels in brown adipose tissue (BAT). Our results showed that during leptin administration, the cumulative food intake and increase of body mass were suppressed while Tb and RMR were unaltered. The proportion of torpid squirrels was not different between two groups. At the end of leptin administration, the expressions of hypothalamic neuropeptide Y and agouti gene-related protein were suppressed. There were no differences in UCP1 mRNA expression or protein content in BAT between groups. Our data suggest that leptin can affect energy intake via hypothalamic neuropeptides, but is not involved in the initiation of hibernation in fattening Daurian ground squirrels. PMID:27033037

  13. Gene structure, recombinant expression and functional characterization of grass carp leptin.

    PubMed

    Li, Guan-Gui; Liang, Xu-Fang; Xie, Qiuling; Li, Guangzhao; Yu, Ying; Lai, Kaaseng

    2010-03-01

    Leptin is an important hormone for the regulation of food intake, energy expenditure and reproduction in mammals, but information regarding its role in teleosts remains scant. In the present study, the gene structures of grass carp (Ctenopharyngodon idellus) and silver carp (Hypophthalmichthys molitrix) leptins were characterized. Recombinant grass carp leptin (rgc-LEP) was expressed in Escherichia coli and purified, and identified by mass spectrometric analysis. A strong anorexic effect on food intake was observed in grass carp on the first day after intraperitoneal (IP) injection of rgc-LEP, but not during the following days. Body weight of the leptin group (LEP group) and the pair-fed group (PF group) showed no difference throughout the experimental period. The acute and chronic effects on the expression of key genes correlating to food intake, energy expenditure, lipid metabolism and digestion were further characterized by real-time PCR. Accordingly, the mRNA levels of neuropeptide Y (NPY), Stearoyl-CoA desaturase 1 (SCD1) and lipoprotein lipase (LPL) were significantly reduced whereas the mRNA levels of uncoupling protein 2 (UCP2), bile salt-activated lipase (BSAL) and fatty acid elongase (ELO) were significantly elevated on the first day after injection. No effect on the expression of these genes (except LPL) was observed on day 13. In contrast to the down-regulation by exogenous leptin in mammals, the mRNA level of grass carp leptin was elevated 5.76-fold on the first day after rgc-LEP treatment. Our results suggest that leptin has an acute effect on the regulation of food intake, energy expenditure and lipid metabolism in grass carp, but the effect can be rapidly counteracted through mechanisms that are currently unknown.

  14. Plasma leptin levels and risk of breast cancer in premenopausal women

    PubMed Central

    Harris, Holly R.; Tworoger, Shelley S.; Hankinson, Susan E.; Rosner, Bernard A.; Michels, Karin B.

    2011-01-01

    Background Body mass index (BMI) is inversely related to the risk of premenopausal breast cancer, but the underlying biological mechanisms of this association are poorly understood. Leptin, a peptide hormone produced primarily by adipocytes, is a potential mediator of the BMI association since BMI and total body fat are positively associated with circulating leptin levels and leptin and its receptor are overexpressed in breast tumors. Methods We conducted a prospective case-control study nested within the Nurses’ Health Study II cohort examining the association between plasma leptin levels in premenopausal women and breast cancer risk. Leptin was measured in blood samples collected between 1996 and 1999. The analysis included 330 incident breast cancer cases diagnosed after blood collection and 636 matched controls. Logistic regression models, controlling for breast cancer risk factors, were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). Results After adjustment for BMI at age 18, weight change since age 18 to blood draw, and other breast cancer risk factors, plasma leptin levels were inversely associated with breast cancer risk (OR for top vs. bottom quartile 0.55; 95% CI 0.31–0.99; p for trend=0.04). Adjustment for BMI at blood draw attenuated the association (OR=0.69; 95% CI 0.38–1.23; p for trend=0.26). Conclusion Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI. PMID:21680707

  15. PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling.

    PubMed

    Hawke, Zoe; Ivanov, Tina R; Bechtold, David A; Dhillon, Harveen; Lowell, Brad B; Luckman, Simon M

    2009-11-25

    The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP(6-38) markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance.

  16. Triiodothyronine modulates the expression of leptin and adiponectin in 3T3-L1 adipocytes

    PubMed Central

    de Oliveira, Miriane; Síbio, Maria Teresa De; Olimpio, Regiane Marques Castro; Moretto, Fernanda Cristina Fontes; Luvizotto, Renata de Azevedo Melo; Nogueira, Celia Regina

    2015-01-01

    Objective To study the effect of different doses of triiodothyronine on gene expression of the adipokines leptin and adiponectin, at different times, and to evaluate the difference in expression between the two adipokines in each group. Methods 3T3-L1 adipocytes were incubated with triiodothyronine at physiological dose (10nM) and supraphysiological doses (100nM or 1,000nM), or without triiodothyronine (control, C) for 0.5, 6, or 24 hours. Leptin and adiponectin mRNA was detected using real-time polymerase chain reaction (RT-PCR). One-way analyses of variance, Tukey’s test or Student’s t test, were used to analyze data, and significance level was set at 5%. Results Leptin levels decreased in the 1,000nM-dose group after 0.5 hour. Adiponectin levels dropped in the 10nM-dose group, but increased at the 100nM dose. After 6 hours, both genes were suppressed in all hormone concentrations. After 24 hours, leptin levels increased at 10, 100 and 1,000nM groups as compared to the control group; and adiponectin levels increased only in the 100nM group as compared to the control group. Conclusion These results demonstrated fast actions of triiodothyronine on the leptin and adiponectin expression, starting at 0.5 hour, at a dose of 1,000nM for leptin and 100nM for adiponectin. Triiodothyronine stimulated or inhibited the expression of adipokines in adipocytes at different times and doses which may be useful to assist in the treatment of obesity, assuming that leptin is increased and adiponectin is decreased, in obesity cases. PMID:25993072

  17. Increased risk of cardiovascular complications in chronic kidney disease: a possible role of leptin.

    PubMed

    Korolczuk, Agnieszka; Dudka, Jaroslaw

    2014-01-01

    Leptin is a small peptide hormone (16 kDa), a product of the obesity gene (Ob), and is mainly synthesized and secreted by adipocytes. It is removed from the blood by the kidneys. The kidney is not only a site of leptin clearance, but also a target organ for its action in different pathophysiological states. Several studies have documented a strong relationship between chronic kidney disease (CKD) and accelerated cardiovascular disease (CVD) defined as a cardiorenal syndrome. Patients with stage 3 and 4 CKD develop cardiovascular complications and are at increased risk of death from CVD. Renal dysfunction promotes several mechanisms responsible for exacerbation of cardiovascular disease. These include activation of the renin-angiotensin system, oxidative stress, elevated asymmetric dimethylarginine (ADMA), low-grade inflammation with increased circulating cytokines, and dyslipidemia. Recently, it has been observed that plasma leptin level is elevated in patients with cardiorenal syndrome. In obesity, hyperleptinemia combined with selective leptin resistance appear to have a critical role in the development and progression of kidney disease, CVD and metabolic syndrome. This has clinical implications for the treatment of obesity-related hypertension and kidney disease. In this paper the role of leptin in chronic kidney disease and accelerated cardiovascular disease is out lined. The link between hyperleptinemia and development and progression of morphologic changes that effect kidney in obese patients is also discussed.

  18. Presence and distribution of leptin and its receptor in the minor salivary glands of the donkey.

    PubMed

    Dall'Aglio, Cecilia; Bazzucchi, Cinzia; Mercati, Francesca; Ceccarelli, Piero

    2015-04-01

    Leptin is a hormone widely diffused in the mammalian body in which it plays functions that go far beyond control of appetite and energy metabolism. The finding that it is present in the major salivary glands of various animal species is of interest for the functional implications that it may imply. Since there are no data on the presence of leptin and its receptor in the minor salivary glands, the aim of this study was to demonstrate their presence and distribution in such glands of donkeys. This latter was chosen as species of reference because the monogastric herbivore shows intense salivation during their masticatory activity. Tissue samples were collected from four adult donkeys, of both sexes, following slaughter. Samples were fixed, embedded in paraffin, and processed for immunohistochemical analysis using primary antibodies directed against leptin and its receptor. Controls for non-specific staining were always included. Leptin and its receptor were found in the minor salivary glands. Their distribution was similar to that described in the major salivary glands of animal species that have been investigated to date. We hypothesized that leptin can play a role in regulating gland function, via an autocrine/paracrine mechanism.

  19. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight

    PubMed Central

    Borer, Katarina T

    2014-01-01

    A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses. PMID:25317239

  20. Regulation of leptin synthesis in white adipose tissue of the female fruit bat, Cynopterus sphinx: role of melatonin with or without insulin.

    PubMed

    Banerjee, A; Udin, S; Krishna, A

    2011-02-01

    Factors regulating leptin synthesis during adipogenesis in wild species are not well known. Studies in the female Cynopterus sphinx bat have shown that it undergoes seasonal changes in its fat deposition and serum leptin and melatonin levels. The aim of the present study was to investigate the hormonal regulation of leptin synthesis by the white adipose tissue during the period of fat deposition in female C. sphinx. This study showed a significant correlation between the seasonal changes in serum melatonin level with the circulating leptin level (r = 0.78; P < 0.05) and with the changes in body fat mass (r = 0.88; P < 0.05) in C. sphinx. A significant correlation between circulating insulin and leptin levels (r = 0.65; P < 0.05) was also found in this species. This in vivo finding suggests that melatonin together with insulin may enhance leptin synthesis by increasing adipose tissue accumulation. The in vitro study showed that melatonin interacts synergistically with insulin in stimulating leptin synthesis by adipose tissue in C. sphinx. The study showed MT(2) receptors in adipose tissue and a stimulatory effect of melatonin on leptin synthesis, which was blocked by treatment with an MT(2) receptor antagonist, suggesting that the effect of melatonin on leptin synthesis by adipose tissue is mediated through the MT(2) receptor in C. sphinx. The in vitro study showed that the synthesis of leptin is directly proportional to the amount of glucose uptake by the adipose tissue. It further showed that melatonin together with insulin synergistically enhanced the leptin synthesis by adipose tissue through phosphorylation of mitogen-activated protein kinase in C. sphinx.

  1. Leptin potentiates astrogenesis in the developing hypothalamus

    PubMed Central

    Rottkamp, Daniele M.; Rudenko, Ivan A.; Maier, Matthew T.; Roshanbin, Sahar; Yulyaningsih, Ernie; Perez, Luz; Valdearcos, Martin; Chua, Streamson; Koliwad, Suneil K.; Xu, Allison W.

    2015-01-01

    Background The proper establishment of hypothalamic feeding circuits during early development has a profound influence on energy homeostasis, and perturbing this process could predispose individuals to obesity and its associated consequences later in life. The maturation of hypothalamic neuronal circuitry in rodents takes place during the initial postnatal weeks, and this coincides with a dramatic surge in the circulating level of leptin, which is known to regulate the outgrowth of key neuronal projections in the maturing hypothalamus. Coincidently, this early postnatal period also marks the rapid proliferation and expansion of astrocytes in the brain. Methods Here we examined the effects of leptin on the proliferative capacity of astrocytes in the developing hypothalamus by treating postnatal mice with leptin. Mutant mice were also generated to conditionally remove leptin receptors from glial fibrillary acidic protein (GFAP)-expressing cells in the postnatal period. Results and conclusions We show that GFAP-expressing cells in the periventricular zone of the 3rd ventricle were responsive to leptin during the initial postnatal week. Leptin enhanced the proliferation of astrocytes in the postnatal hypothalamus and conditional removal of leptin receptors from GFAP-expressing cells during early postnatal period limited astrocyte proliferation. While increasing evidence demonstrates a direct role of leptin in regulating astrocytes in the adult brain, and given the essential function of astrocytes in modulating neuronal function and connectivity, our study indicates that leptin may exert its metabolic effects, in part, by promoting hypothalamic astrogenesis during early postnatal development. PMID:26629411

  2. Connecting leptin signaling to biological function

    PubMed Central

    Allison, Margaret B.; Myers, Martin G.

    2014-01-01

    Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor, LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling (SOCS) proteins and protein tyrosine phosphatases (PTPases) also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models which have been used to elucidate these functions in vivo. PMID:25232147

  3. Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments.

    PubMed

    Vázquez, María Jesús; Romero-Ruiz, Antonio; Tena-Sempere, Manuel

    2015-01-01

    As an essential function for perpetuation of species, reproduction, including puberty onset, is sensitive to the size of body energy stores and the metabolic state of the organism. Accordingly, impaired energy homeostasis, ranging from extreme leanness, such as in anorexia or cachexia, to morbid obesity has an impact on the timing of puberty and is often associated to fertility problems. The neuroendocrine basis for such phenomenon is the close connection between numerous metabolic hormones and nutritional cues with the various elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. Yet, despite previous fragmentary knowledge, it was only the discovery of the adipose-hormone, leptin, in 1994 what revolutionized our understanding on how metabolic and reproductive systems closely interplay and allowed the definition of the neurohormonal causes of perturbations of puberty and fertility in conditions of impaired body energy homeostasis. In this article, we aim to provide a synoptic view of the mechanisms whereby leptin engages in the regulation of different elements of the HPG axis, with special attention to its effects and mechanisms of action on the different elements of the reproductive brain and its proven direct effects in the gonads. In addition, we will summarize the state-of-the-art regarding the putative roles of leptin during gestation, including its potential function as placental hormone. Finally, comments will be made on the eventual leptin alterations in reproductive disorders, with special attention to the polycystic ovary syndrome (PCOS), a disease in which reproductive, metabolic and neuroendocrine alterations are commonly observed. All in all, we intend to provide an updated account of our knowledge on the physiological roles of leptin in the metabolic regulation of the reproductive axis and its eventual pathophysiological implications in prevalent reproductive disorders, such as PCOS.

  4. Leptin stimulates uncoupling protein-2 mRNA expression and Krebs cycle activity and inhibits lipid synthesis in isolated rat white adipocytes.

    PubMed

    Ceddia, R B; William, W N; Lima, F B; Flandin, P; Curi, R; Giacobino, J P

    2000-10-01

    The treatment of rats and mice with leptin causes dramatic body fat reduction and in some cases even disappearance of fat tissue. Here, we report the effects of leptin (10 and 100 ng.mL-1) on isolated rat adipocytes maintained for 15 h in culture. Leptin decreased the incorporation of acetate into total lipids by 30%. A reduction in this incorporation (42%) was still observed after the leptin-cultivated adipocytes were exposed to a supra-physiological insulin concentration (10 000 microU.mL-1). On the other hand, leptin increased acetate degradation by 69% and the maximal activity of citrate synthase by 50% in isolated adipocytes. It also increased oleate degradation by 35 and 50% at concentrations of 10 and 100 ng. mL-1, respectively. Eventually, leptin upregulated the uncoupling protein-2 (UCP2) mRNA level by 63% and had no effect on uncoupling protein-3 (UCP3) mRNA in isolated adipocytes. The upregulation of UCP2 mRNA might have contributed to the stimulation of acetate and fatty acid degradation by leptin. The peripheral effects of leptin observed in this study are in line with the general energy dissipating role postulated for this hormone and for UCP2. They suggest mechanisms by which adipocytes regulate their fat content by an autocrine pathway without the participation of the central nervous system.

  5. Effects of Gn-RH, TRH, and CRF administration on plasma leptin levels in lean and obese women.

    PubMed

    Komorowski, J; Jankiewicz-Wika, J; Stepień, H

    2000-04-01

    Leptin, a hormone which is produced by adipose tissue, has been shown to inhibit food intake, increase energy expenditure and influence the function of hypothalamo-pituitary-gonadal, -thyroid, and -adrenal systems. We have examined the association between leptin concentrations (RIA method) and levels of different hormones using standard Gn-RH, TRH and CRF tests (at 0, 30, 60, and 120 min) in regularly menstruating 10 lean and 10 obese premenopausal women in follicular phase. FSH, LH, estradiol (E2) and progesterone (P) concentrations in Gn-RH test; TSH, PRL, fT3, fT4 in TRH test; ACTH, DHEA-S, cortisol in CRF test were measured by RIA, ELISA or IRMA methods. The obese subjects had thicker four skinfolds, higher fat content in the body, and bigger BMI, compared to the lean females. Gn-RH test: We have noted higher basal leptin values in obese women than in lean subjects, which was stable during the Gn-RH test. In the same blood specimen, basal insulin concentrations did not differ between the tested groups of patients. There were no correlations between E(2), P, or gonadotropins and plasma leptin concentrations between both groups of patients. We have revealed the negative correlation between LH mobilization (maximal incremental values over basal levels; Delta%) and baseline leptin concentrations in all observed subjects. TRH test: In both groups of patients the leptin levels decreased at 120 min of TRH administration. We have noted diminished PRL and TSH mobilisation in obese subjects in comparison to the controls. In all females (n = 20) the correlations between TSH or PRL mobilization and BMI, skinfold thickness and the mass of body fat in kg were negative. In obese subjects only we observed the positive correlations between fT(3)concentrations at 60 and 120 min of the test or Delta% of fT(3)and leptin levels. CRF test: In obese females, we noted higher basal ACTH and cortisol concentrations with decreased mobilization (Delta%) of ACTH or cortisol, as compared to

  6. Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass.

    PubMed

    Lahlou, N; Clement, K; Carel, J C; Vaisse, C; Lotton, C; Le Bihan, Y; Basdevant, A; Lebouc, Y; Froguel, P; Roger, M; Guy-Grand, B

    2000-08-01

    Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity. PMID:10923636

  7. Associations of Testosterone and Sex Hormone Binding Globulin with Adipose Tissue Hormones in Midlife Women

    PubMed Central

    Wildman, Rachel P.; Wang, Dan; Fernandez, Ivonne; Mancuso, Peter; Santoro, Nanette; Scherer, Philipp E.; Sowers, MaryFran R.

    2014-01-01

    Objective Regulators of adipose tissue hormones remain incompletely understood, but may include sex hormones. As adipose tissue hormones have been shown to contribute to numerous metabolic and cardiovascular disorders, understanding their regulation in midlife women is of clinical importance. Therefore, we assessed the associations between testosterone (T) and sex hormone binding globulin (SHBG) with leptin, high molecular weight (HMW) adiponectin, and the soluble form of the leptin receptor (sOB-R) in healthy midlife women. Design and Methods Cross-sectional analyses were performed using data from 1,881 midlife women (average age 52.6 (±2.7) years) attending the sixth Annual follow-up visit of the multiethnic Study of Women’s Health Across the Nation. Results T was weakly negatively associated with both HMW adiponectin and sOB-R (r = −0.12 and r = −0.10, respectively; P < 0.001 for both), and positively associated with leptin (r = 0.17; P < 0.001). SHBG was more strongly and positively associated with both HMW adiponectin and sOB-R (r = 0.29 and r = 0.24, respectively; P < 0.001 for both), and more strongly and negatively associated with leptin (r = −0.27; P < 0.001). Adjustment for fat mass, insulin resistance, or waist circumference only partially diminished associations with HMW adiponectin and sOB-R, but attenuated associations with leptin. In conclusion, in these midlife women, lower SHBG values, and to a lesser extent, higher T levels, were associated with lower, or less favorable, levels of adiponectin and sOB-R, independent of fat mass. Conclusions These data suggest that variation in these adipose hormones resulting from lower SHBG levels, and possibly, though less likely, greater androgenicity, may contribute to susceptibility for metabolic and cardiovascular outcomes during midlife in women. PMID:23592672

  8. 20 years of leptin: Role of leptin in cardiomyocyte physiology and physiopathology.

    PubMed

    Feijóo-Bandín, S; Portolés, M; Roselló-Lletí, E; Rivera, M; González-Juanatey, J R; Lago, F

    2015-11-01

    Since the discovery of leptin in 1994 by Zhang et al., there have been a number of reports showing its implication in the development of a wide range of cardiovascular diseases. However, there exists some controversy about how leptin can induce or preserve cardiovascular function, as different authors have found contradictory results about leptin beneficial or detrimental effects in leptin deficient/resistant murine models and in wild type tissue and cardiomyocytes. Here, we will focus on the main discoveries about the leptin functions at cardiac level within the last two decades, focusing on its role in cardiac metabolism, remodeling and contractile function.

  9. Plasma leptin levels and free leptin index in women with Alzheimer's disease.

    PubMed

    Baranowska-Bik, Agnieszka; Bik, Wojciech; Styczynska, Maria; Chodakowska-Zebrowska, Malgorzata; Barcikowska, Maria; Wolinska-Witort, Ewa; Kalisz, Malgorzata; Martynska, Lidia; Baranowska, Boguslawa

    2015-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by irreversible and progressive loss of memory and other cognitive functions. Controversies still exist on the precise mechanisms contributing to neurodegeneration. Obesity and disturbances in metabolic homeostasis are thought to be AD risk factors. Adipokine leptin has receptors in the brain, also in the regions related to AD. Leptin may protect against AD. The aim was to assess leptin and soluble leptin receptor levels in plasma as well as free leptin index (FLI) in correlation with metabolic status of women diagnosed with Alzheimer's disease. Eighteen women with moderate to severe stage of AD, 40 women with AD at early stage, and 42 female controls, matched for age and body mass index, participated in the study. Leptin and soluble leptin receptor levels were measured with RIA and IRMA, respectively. Then, FLI was calculated. In addition, metabolic parameters (lipid profile, glucose and insulin concentrations, HOMA-IR) were estimated. Clinical and anthropometric data were collected. The Mini-Mental State Examination (MMSE) as a cognitive impairment measurement was performed. Correlations with both leptin and FLI, and MMSE, clinical and biochemical parameters were evaluated. Leptin levels and FLI were significantly lower and leptin receptor concentrations were higher in AD subjects when compared with the controls. In AD group leptin, soluble leptin receptor and FLI correlated with selected metabolic parameters but not with MMSE. We conclude that alterations in leptin, leptin receptor, and FLI were the most intensified in advanced AD. However, these results did not correlate with dementia stage measured with MMSE. Therefore, further intensive research is needed to explain the mechanisms involved in this phenomenon.

  10. [Soft tissues, hormones and the skeleton].

    PubMed

    Zofková, I

    2012-02-01

    Mechanical load activates bone modeling and increases bone strength. Thus physical activity is extremely important for overall bone health. Muscle volume and muscle contraction are closely related to bone mineral density in men and women, although these relationships are more significat in men. The muscle-bone unit has been defined as a functional system, in which both components are under control of the somatotropin-IGF-I system, androgens and D hormone. These endocrine systems play, via the muscle-bone unit, an important role in development of the skeleton and its stability in adulthood. That is why deficiency of any of these hormonal systems, or reduced physical activity (mainly in childhood) could seriously affect bone density and quality. Bone is also under control of adipose tissue, which modulates its metabolism via mechanical load and more importantly via adipocytokines (leptin, adiponectin and rezistin). Leptin increases bone formation by activation of osteoblasts. This direct effect of leptin is amplified by stimulation of the β-1 adrenergic system, which inhibits the negative osteotropic effects of neuropeptide Y. On the other hand, leptin also activates β-2 adrenergic receptors, which increase bone resorption. In humans, the overall osteo-anabolic effect of leptin tends to be dominant. Furthermore, leptin has a principal role in the start of puberty in girls and maturation, remodeling and development of the female skeleton. Adiponectin (and probably rezistin) has an unambiguous deteriorating effect on the skeleton. Further studies are needed to confirm the clinical importance of soft tissues relative to the integrity of the skeleton.

  11. Leptin suppresses non-apoptotic cell death in ischemic rat cardiomyocytes by reduction of iPLA{sub 2} activity

    SciTech Connect

    Takatani-Nakase, Tomoka Takahashi, Koichi

    2015-07-17

    Caspase-independent, non-apoptotic cell death is an important therapeutic target in myocardial ischemia. Leptin, an adipose-derived hormone, is known to exhibit cytoprotective effects on the ischemic heart, but the mechanisms are poorly understood. In this research, we found that pretreatment of leptin strongly suppressed ischemic-augmented nuclear shrinkage and non-apoptotic cell death on cardiomyocytes. Leptin was also shown to significantly inhibit the activity of iPLA{sub 2}, which is considered to play crucial roles in non-apoptotic cell death, resulting in effective prevention of ischemia-induced myocyte death. These findings provide the first evidence of a protective mechanism of leptin against ischemia-induced non-apoptotic cardiomyocyte death. - Highlights: • Myocardial ischemia-model induces in caspase-independent, non-apoptotic cell death. • Leptin strongly inhibits ischemic-augmented non-apoptotic cell death. • Leptin reduces iPLA{sub 2} activity, leading to avoidance of non-apoptotic cell death.

  12. Effect of cyproheptadine on serum leptin levels.

    PubMed

    Calka, Omer; Metin, Ahmet; Dülger, Haluk; Erkoç, Reha

    2005-01-01

    Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship.

  13. The Effects of Leptin on Breastfeeding Behaviour.

    PubMed

    Cannon, Anna M; Kakulas, Foteini; Hepworth, Anna R; Lai, Ching Tat; Hartmann, Peter E; Geddes, Donna T

    2015-09-30

    Breastfed infants have a reduced risk of becoming overweight and/or obese later in life. This protective effect has been partly attributed to leptin present in breastmilk. This study investigated 24-h variations of skim milk leptin and its relationship with breastmilk macronutrients and infant breastfeeding patterns. Exclusive breastfeeding mothers of term singletons (n = 19; age 10 ± 5 weeks) collected pre- and post-feed breastmilk samples for every breastfeed over a 24-h period and test-weighed their infants to determine milk intake at every breastfeed over a 24-h period. Samples (n = 454) were analysed for leptin, protein, lactose and fat content. Skim milk leptin concentration did not change with feeding (p = 0.184). However, larger feed volumes (>105 g) were associated with a decrease in post-feed leptin levels (p = 0.009). There was no relationship between the change in leptin levels and change in protein (p = 0.313) or lactose levels (p = 0.587) between pre- and post-feed milk, but there was a trend for a positive association with changes in milk fat content (p = 0.056). Leptin concentration significantly increased at night (p < 0.001) indicating a possible 24-h pattern. Leptin dose (ng) was not associated with the time between feeds (p = 0.232). Further research should include analysis of whole breastmilk and other breastmilk fractions to extend these findings.

  14. Regulation and Role of Leptin: Poultry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The recently discovered protein, leptin, which is secreted by fat cells, has been implicated in the regulation of appetite, energy balance, and the neuroendocrine axis in poultry. The leptin receptor has been cloned and is a member of the class I cytokine family of receptors is found in the brain a...

  15. Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist.

    PubMed

    Foskolos, A; Ehrhardt, R A; Hileman, S M; Gertler, A; Boisclair, Y R

    2015-11-01

    Ruminants remain productive during the energy insufficiency of late pregnancy or early lactation by evoking metabolic adaptations sparing available energy and nutrients (e.g. higher metabolic efficiency and induction of insulin resistance). A deficit in central leptin signaling triggers these adaptations in rodents but whether it does in ruminants remains unclear. To address this issue, five mature ewes were implanted with intracerebroventricular (ICV) cannula in the third ventricle. They were used in two experiments with an ovine leptin antagonist (OLA) when well-conditioned (average body condition score of 3.7 on a 5 point scale). The first experiment tested the ability of OLA to antagonize leptin under in vivo conditions. Ewes received continuous ICV infusion of artificial cerebrospinal fluid (aCSF), ovine leptin (4 µg/h) or the combination of ovine leptin (4 µg/h) and its mutant version OLA (40 µg/h) for 48 h. Dry matter intake (DMI) was measured every day and blood samples were collected on the last day of infusion. ICV infusion of leptin reduced DMI by 24% (P < 0.05), and this effect was completely abolished by OLA co-infusion. A second experiment tested whether a reduction in endogenous leptin signaling in the brain triggers metabolic adaptations. This involved continuous ICV infusions of aCSF or OLA alone (40 µg/h) for 4 consecutive days. The infusion of OLA did not alter voluntary DMI over the treatment period or on any individual day. OLA did not affect plasma variables indicative of insulin action (glucose, non-esterified fatty acids, insulin and the disposition of plasma glucose during an insulin tolerance test) or plasma cortisol, but tended to reduce plasma triiodothyronine and thyroxine (P < 0.07). Overall, these data show that a reduction of central leptin signaling has little impact on insulin action in well-conditioned mature sheep. They also raise the possibility that reduced central leptin signaling plays a role in controlling thyroid

  16. Leptin is required for hypothalamic regulation of miRNAs targeting POMC 3′UTR

    PubMed Central

    Derghal, Adel; Djelloul, Mehdi; Airault, Coraline; Pierre, Clément; Dallaporta, Michel; Troadec, Jean-Denis; Tillement, Vanessa; Tardivel, Catherine; Bariohay, Bruno; Trouslard, Jérôme; Mounien, Lourdes

    2015-01-01

    The central nervous system (CNS) monitors modifications in metabolic parameters or hormone levels and elicits adaptive responses such as food intake regulation. Particularly, within the hypothalamus, leptin modulates the activity of pro-opiomelanocortin (POMC) neurons which are critical regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the POMC gene causes hyperphagia and obesity. MicroRNAs (miRNAs) are short noncoding RNA molecules that post-transcriptionally repress the expression of genes by binding to 3′-untranslated regions (3′UTR) of the target mRNAs. However, little is known regarding the role of miRNAs that target POMC 3′UTR in the central control energy homeostasis. Particularly, their interaction with the leptin signaling pathway remain unclear. First, we used common prediction programs to search for potential miRNAs target sites on 3′UTR of POMC mRNA. This screening identified a set of conserved miRNAs seed sequences for mir-383, mir-384-3p, and mir-488. We observed that mir-383, mir-384-3p, and mir-488 are up-regulated in the hypothalamus of leptin deficient ob/ob mice. In accordance with these observations, we also showed that mir-383, mir-384-3p, and mir-488 were increased in db/db mice that exhibit a non-functional leptin receptor. The intraperitoneal injection of leptin down-regulated the expression of these miRNAs of interest in the hypothalamus of ob/ob mice showing the involvement of leptin in the expression of mir-383, mir-384-3p, and mir-488. Finally, the evaluation of responsivity to intracerebroventricular administration of leptin exhibited that a chronic treatment with leptin decreased mir-488 expression in hypothalamus of C57BL/6 mice. In summary, these results suggest that leptin modulates the expression of miRNAs that target POMC mRNA in hypothalamus. PMID:25999818

  17. [Leptin: a link between obesity and osteoarthritis?].

    PubMed

    Terlain, Bernard; Presle, Nathalie; Pottie, Pascale; Mainard, Didier; Netter, Patrick

    2006-10-01

    In addition to aging, obesity is one of the most common underlying causes of osteoarthritis (OA). Mechanical loading, together with biochemical and systemic factors linked to altered lipid metabolism, are thought to contribute to the onset of OA. It has been suggested that OA is a systemic metabolic disease associated with lipid disorders affecting joint homeostasis. These gradual changes may be due to the local effect of adipokines, and especially leptin. Indeed, their relative levels in joints differ from that found in plasma. In particular, leptin levels are increased and adiponectin and resistin levels are reduced This hypothesis is supported by--leptin overexpression in OA cartilage and its correlation with the degree of cartilage destruction,--abundant leptin synthesis by osteophytes, and--the high leptin levels found in OA joints from female patients. This link between OA and adipokines provides new leads regarding the prevention of OA and the identification of new drug targets.

  18. [Role of leptin in human reproduction (anorexia, bulimia)].

    PubMed

    Pilka, L; Rumpík, D; Pilka, R

    2012-12-01

    Leptin may act as the critical link between adipose tissue and the reproductive system, indicating whether adequate energy reserves are presenting for normal reproductive functions. Future interventional studies involving leptin administration are excepted to further clarify this role of leptin and may provide new therapeutic options for the reproductive dysfunctions associated with states of relative leptin deficiency or resistance.

  19. Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats.

    PubMed

    Haque, Zeba; Akbar, Nazia; Yasmin, Farzana; Haleem, Muhammad A; Haleem, Darakhshan J

    2013-05-01

    Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light-dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light-dark transition test were reversed by exogenous leptin in a dose-dependent (0.1-0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders.

  20. Prenatal lipid-based nutrient supplements increase cord leptin concentration in pregnant women from rural Burkina Faso.

    PubMed

    Huybregts, Lieven; Roberfroid, Dominique; Lanou, Hermann; Meda, Nicolas; Taes, Youri; Valea, Innocent; D'Alessandro, Umberto; Kolsteren, Patrick; Van Camp, John

    2013-05-01

    In developing countries, prenatal lipid-based nutrient supplements (LNSs) were shown to increase birth size; however, the mechanism of this effect remains unknown. Cord blood hormone concentrations are strongly associated with birth size. Therefore, we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development. We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a randomized, controlled design including 197 pregnant women from rural Burkina Faso. Insulin-like growth factors (IGF) I and II, their binding proteins IGFBP-1 and IGFBP-3, leptin, cortisol, and insulin were quantified in cord sera using immunoassays. LNS was associated with higher cord blood leptin mainly in primigravidae (+57%; P = 0.02) and women from the highest tertile of BMI at study inclusion (+41%; P = 0.02). We did not find any significant LNS effects on other measured cord hormones. The observed increase in cord leptin was associated with a significantly higher birth weight. Cord sera from small-for-gestational age newborns had lower median IGF-I (-9 μg/L; P = 0.003), IGF-II (-79 μg/L; P = 0.003), IGFBP-3 (-0.7 μg/L; P = 0.007), and leptin (-1.0 μg/L; P = 0.016) concentrations but higher median cortisol (+18 μg/L; P = 0.037) concentrations compared with normally grown newborns. Prenatal LNS resulted in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion. The elevated leptin concentrations could point toward a higher neonatal fat mass.

  1. Novel leptin OB3 peptide-induced signaling and progression in thyroid cancers: Comparison with leptin

    PubMed Central

    Hsieh, Meng-Ti; Lai, Hsuan-Yu; Ke, Chien-Chih; Crawford, Dana R.; Lee, Oscar K.; Fu, Earl; Mousa, Shaker A.; Grasso, Patricia; Liu, Leroy F.; Chang, Heng-Yu; Tang, Heng-Yuan; Lin, Hung-Yun; Davis, Paul J.

    2016-01-01

    Obesity results in increased secretion of cytokines from adipose tissue and is a risk factor for various cancers. Leptin is largely produced by adipose tissue and cancer cells. It induces cell proliferation and may serve to induce various cancers. OB3-leptin peptide (OB3) is a new class of functional leptin peptide. However, its mitogenic effect has not been determined. In the present study, because of a close link between leptin and the hypothalamic-pituitary-thyroid axis, OB3 was compared with leptin in different thyroid cancer cells for gene expression, proliferation and invasion. Neither agent stimulated cell proliferation. Leptin stimulated cell invasion, but reduced adhesion in anaplastic thyroid cancer cells. Activated ERK1/2 and STAT3 contributed to leptin-induced invasion. In contrast, OB3 did not affect expression of genes involved in proliferation and invasion. In vivo studies in the mouse showed that leptin, but not OB3, significantly increased circulating levels of thyrotropin (TSH), a growth factor for thyroid cancer. In summary, OB3 is a derivative of leptin that importantly lacks the mitogenic effects of leptin on thyroid cancer cells. PMID:27050378

  2. Akt Activation and Inhibition of Cytochrome C Release: Mechanistic Insights into Leptin-promoted Survival of Type II Alveolar Epithelial Cells.

    PubMed

    Chen, Hui; Liang, Zhen-Wei; Wang, Zhen-Hua; Zhang, Jian-Ping; Hu, Bo; Xing, Xiang-Bin; Cai, Wei-Bin

    2015-10-01

    Fetal growth restriction (FGR) increases the risk of perinatal death, partly due to defects in lung development. Leptin, a polypeptide hormone, is involved in fetal lung development. We previously demonstrated that treatment with exogenous leptin during gestation significantly promotes fetal lung maturity in the rat model of FGR. In this study, to delineate the molecular pathways through which leptin may enhance fetal lung development, we investigated the impact of leptin treatment on the survival of type II alveolar epithelial cells (AECs), essential leptin-responsive cells involved in lung development, in a rat model of FGR. The rat model of FGR was induced in pregnant Sprague-Dawley rats by partial uterine artery and vein ligation. In vivo and in vitro analyses of fetal lung tissues and freshly-isolated cultured AECs, respectively, showed that leptin protects type II AECs from hypoxia-induced apoptosis. Further molecular studies revealed the role of Akt activation in the leptin-mediated promotion of survival of type II AECs. The data also showed that the anti-apoptotic effects of leptin are dependent on phosphoinositol 3-kinase (PI3K) activation, and involve the down-regulation of caspases 3 and 9, upregulation of pro-survival proteins Bcl-2, and p-Bad, and inhibition of the release of cytochrome c from mitochondria. Taken together, our data suggested that leptin enhances the maturity of fetal lungs by mediating the regulation of caspase-3 and -9 during hypoxia-induced apoptosis of type II AECs and provide support for the potential of leptin as a therapeutic agent for promoting lung development in FGR.

  3. Diet-induced obese mice retain endogenous leptin action.

    PubMed

    Ottaway, Nickki; Mahbod, Parinaz; Rivero, Belen; Norman, Lee Ann; Gertler, Arieh; D'Alessio, David A; Perez-Tilve, Diego

    2015-06-01

    Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice.

  4. Diurnal Intermittent Fasting during Ramadan: The Effects on Leptin and Ghrelin Levels

    PubMed Central

    Alzoghaibi, Mohammed A.; Pandi-Perumal, Seithikurippu R.; Sharif, Munir M.; BaHammam, Ahmed S.

    2014-01-01

    We aimed to assess the effect of Islamic intermittent fasting, during and outside of Ramadan, on plasma levels of leptin and ghrelin while controlling for several potential confounding variables. Eight healthy male volunteers with a mean age of 26.6±4.9 years reported to the sleep disorders center (SDC) at King Saud University on four occasions: 1) adaptation; 2) 4 weeks before Ramadan while performing Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non-fasting baseline) (BL); and 4) during the second week of Ramadan while fasting. Plasma leptin and ghrelin levels were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00. During BLF, there were significant reductions in plasma leptin concentrations at 22:00 and 02:00 compared with the baseline concentrations (at 22:00: 194.2±177.2 vs. 146.7±174.5; at 02:00: 203.8±189.5 vs. 168.1±178.1; p<0.05). During Ramadan, there was a significant reduction in plasma leptin levels at 22:00 (194.2±177.2 vs. 132.6±130.4, p<0.05). No significant difference in plasma ghrelin concentrations was detected during the BL, BLF, or Ramadan periods. Cosinor analyses of leptin and ghrelin plasma levels revealed no significant changes in the acrophases of the hormones during the three periods. The nocturnal reduction in plasma leptin levels during fasting may be the result of the changes in meal times during fasting. PMID:24637892

  5. Leptin differentially regulates NPY secretion in hypothalamic cell lines through distinct intracellular signal transduction pathways.

    PubMed

    Dhillon, Sandeep S; Belsham, Denise D

    2011-04-11

    Leptin acts as a key peripheral hormone in distinct neurons in the hypothalamus to modulate both reproductive function and energy homeostasis. The control of neuropeptide Y (NPY) secretion is an example of a process that can be differentially regulated by leptin. In order to further understand these distinct modulatory effects, we have used immortalized, neuronal hypothalamic cell lines expressing NPY, mHypoE-38 and mHypoE-46. We found that these cell lines express the endogenous leptin receptor, ObRb, and secrete detectable levels of NPY. We exposed the neurons to 100nM leptin for 1h and determined that the basal levels of NPY in the cell lines were differentially regulated: NPY secretion was inhibited in mHypoE-46 neurons, whereas NPY secretion was induced in the mHypoE-38 neurons. In order to determine the mechanisms involved in the divergent regulation of NPY release, we analyzed the activity of a number of signaling components using phospho-specific antibodies directed towards specific proteins in the MAP kinase, PI3K, and AMPK pathways, among others. We found that leptin activated a different combination of second messengers in each cell line. Importantly, we could link the regulation of NPY secretion to different signaling pathways, AMPK in the mHypoE-46 and both MAPK and PI3K in the mHypoE-38 neurons. This is the first demonstration that leptin can specifically regulate individual NPY neuron secretory responses through distinct signaling pathways.

  6. Correlation between serum leptin and bone mineral density in hemodialysis patients

    PubMed Central

    Ghorban-Sabbagh, Mahin; Nazemian, Fatemeh; Naghibi, Massih; Shakeri, Mohammad-Taghi; Ahmadi-Simab, Saeedeh; Javidi-Dasht-Bayaz, Reza

    2016-01-01

    Introduction: For diagnosing of specific types of bone lesions in hemodialysis (HD) patients, it is necessary to conduct a bone biopsy as the gold standard method. However, it is an invasive procedure. While different markers have been suggested as alternative methods, none of them has been selected. The frequency of hip fractures is 80 fold in HD patients who have two-fold mortality as compared with general population. Objectives: Recently, serum leptin has been suggested as a bone density marker. This study tries to confirm this proposal. Patients and Methods: In this study about 104 HD patients (53.8% male and 46.2% female) were enrolled. The average age was 38.28±7.89 years. Serum leptin, bone alkaline phosphatase, intact parathyroid hormone (iPTH), 25(OH)D, calcium, phosphorus and bone mineral density (BMD) (at the femoral neck and lumbar spine, as measured by dual-energy x-ray absorptiometry [DXA]) were assessed. Results: Analysis by polynomial regression revealed no correlation between BMD Z-score at two points and serum leptin level. According to the thresholds of 25 ng/mL and 18-24 ng/mL in some studies, we detected 25 ng/mL as the threshold in our patients. Under this threshold, the leptin effect on bone mass was negative, and above the threshold of 25 ng/mL, we found leptin had positive effect on bone mass. Conclusion: In this investigation, we found, leptin has a bimodal effect on bone mass. Cortical bones assessment may be a better option for assessment. PMID:27689105

  7. Exogenous leptin controls the development of the small intestine in neonatal piglets.

    PubMed

    Woliński, J; Biernat, M; Guilloteau, P; Weström, B R; Zabielski, R

    2003-05-01

    Leptin, a hormone produced and secreted by adipose tIssue, muscles and stomach, is involved in the regulation of adipose tIssue mass, food intake and body weight in neonatal animals. It is also produced in the mammary glands and secreted into the colostrum and milk. Since leptin receptors are widely distributed in the small intestine mucosa, the aim of the present study was to investigate the effect of exogenous leptin on the development of the small intestine in neonatal piglets. Male neonatal piglets were fed with sow's milk or artificial milk formula. Every 8 h the latter received either vehicle or leptin (2 or 10 microg/kg body weight). The animals were either killed after 6 days of treatment and the small intestine sampled for histology and brush border enzyme activities or were tested for marker molecule (Na-fluorescein and BSA) absorption in vivo. Feeding milk formula slowed the maturation of small intestinal mucosa compared with feeding sow's milk. However, after leptin treatment the length of the small intestine was increased, and intestinal villi length, but not crypt size, was reduced compared with controls. The mitotic index was increased and the percentage of vacuolated enterocytes was reduced in the entire small intestine. Enterocyte brush border protease and lactase activities were reduced in the jejunum. Na-fluorescein marker molecule absorption did not change but that of BSA was reduced 3.8-fold. In conclusion, exogenous leptin administered in physiological doses reversed the maturation of the small intestinal mucosa to the range found in sow-reared piglets.

  8. Diurnal intermittent fasting during Ramadan: the effects on leptin and ghrelin levels.

    PubMed

    Alzoghaibi, Mohammed A; Pandi-Perumal, Seithikurippu R; Sharif, Munir M; BaHammam, Ahmed S

    2014-01-01

    We aimed to assess the effect of Islamic intermittent fasting, during and outside of Ramadan, on plasma levels of leptin and ghrelin while controlling for several potential confounding variables. Eight healthy male volunteers with a mean age of 26.6±4.9 years reported to the sleep disorders center (SDC) at King Saud University on four occasions: 1) adaptation; 2) 4 weeks before Ramadan while performing Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non-fasting baseline) (BL); and 4) during the second week of Ramadan while fasting. Plasma leptin and ghrelin levels were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00. During BLF, there were significant reductions in plasma leptin concentrations at 22:00 and 02:00 compared with the baseline concentrations (at 22:00: 194.2±177.2 vs. 146.7±174.5; at 02:00: 203.8±189.5 vs. 168.1±178.1; p<0.05). During Ramadan, there was a significant reduction in plasma leptin levels at 22:00 (194.2±177.2 vs. 132.6±130.4, p<0.05). No significant difference in plasma ghrelin concentrations was detected during the BL, BLF, or Ramadan periods. Cosinor analyses of leptin and ghrelin plasma levels revealed no significant changes in the acrophases of the hormones during the three periods. The nocturnal reduction in plasma leptin levels during fasting may be the result of the changes in meal times during fasting. PMID:24637892

  9. The Role of BDNF, Leptin, and Catecholamines in Reward Learning in Bulimia Nervosa

    PubMed Central

    Grob, Simona; Milos, Gabriella; Schnyder, Ulrich; Eckert, Anne; Lang, Undine; Hasler, Gregor

    2015-01-01

    Background: A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin. Methods: Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast. Results: AMPT–induced differences in plasma BDNF levels were positively correlated with the AMPT–induced differences in reward learning in the whole sample (P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004). Conclusions: This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls. PMID:25522424

  10. Leptin and leptin receptor: Analysis of a structure to function relationship in interaction and evolution from humans to fish

    PubMed Central

    Prokop, JW; Duff, RJ; Ball, HC; Copeland, DL; Londraville, RL

    2012-01-01

    Leptin is a circulating protein which regulates dietary intake through binding the leptin receptor. Numerous labs have used known structures and mutagenesis to study this binding process in common animal models (human, mouse and rat). Understanding this binding process in other vertebrate species will allow for a better understanding of leptin and leptin receptor function. The binding site between leptin and leptin receptor is highly conserved in mammals as confirmed through sequence alignments mapped onto structures of both leptin and leptin receptor. More variation in this interaction is found in lizard and frog sequences. Using our models, we show that the avian leptin sequences have far less variation in the binding site than does the leptin receptor. This analysis further suggests that avian leptins are artifactual. In fish, gene duplication events have led to the expression of multiple leptin proteins. These multiple leptin proteins have variation in the regions interacting with leptin receptor. In zebrafish and the Japanese rice fish, we propose that leptin A has a higher binding energy than does B. Differing binding energies are evidence of either divergent functions, different binding confirmations, or other protein partners of leptin B. PMID:23085324

  11. Two leptin genes and a leptin receptor gene of female chub mackerel (Scomber japonicus): Molecular cloning, tissue distribution and expression in different obesity indices and pubertal stages.

    PubMed

    Ohga, Hirofumi; Matsumori, Kojiro; Kodama, Ryoko; Kitano, Hajime; Nagano, Naoki; Yamaguchi, Akihiko; Matsuyama, Michiya

    2015-10-01

    Leptin is a hormone produced by fat cells that regulates the amount of fat stored in the body and conveys nutritional status to the reproductive axis in mammals. In the present study we identified two subtypes of leptin genes (lepa and lepb) and a leptin receptor gene (lepr) from chub mackerel (Scomber japonicus) and there gene expression under different feeding conditions (control and high-feed) and pubertal development stages was analyzed using quantitative real-time PCR. The protein lengths of LepA, LepB and LepR were 161 amino acids (aa), 163 aa and 1149 aa, respectively and both leptin subtypes shared only 15% similarity in aa sequences. In pubertal females, lepa was expressed in the brain, pituitary gland, liver, adipose tissue and ovary; however, in adult (gonadal maturation after the second in the life) females, lepa was expressed only in the liver. lepb was expressed primarily in the brain of all fish tested and was expressed strongly in the adipose tissue of adults. lepr was characterized by expression in the pituitary. The high-feed group showed a high conditioning factor level; unexpectedly, hepatic lepa and brain lepr were significantly more weakly expressed compared with the control-feed group. Furthermore, the expression levels of lepa, lepb and lepr genes showed no significant differences between pre-pubertal and post-pubertal fish. On the other hand, pituitary fshβ and lhβ showed no significant differences between different feeding groups of pre-pubertal fish. In contrast, fshβ and lhβ expressed abundantly in the post-pubertal fish of control feed group. Based on these results, whether leptin plays an important role in the nutritional status and pubertal onset of chub mackerel remains unknown.

  12. Leptin stimulates endothelin-1 expression via extracellular signal-regulated kinase by epidermal growth factor receptor transactivation in rat aortic smooth muscle cells.

    PubMed

    Chao, Hung-Hsing; Hong, Hong-Jye; Liu, Ju-Chi; Lin, Jia-Wei; Chen, Yen-Ling; Chiu, Wen-Ta; Wu, Chieh-Hsi; Shyu, Kou-Gi; Cheng, Tzu-Hurng

    2007-11-14

    Obesity is a major risk factor for the development of hypertension. Recent studies have suggested that leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is related to the pathogenesis of obesity-related hypertension. However, the signaling mechanisms underlying the effects of leptin remain to be extensively examined. In this study, we found that leptin induced extracellular signal-regulated kinase phosphorylation and endothelin-1 expression in rat aortic smooth muscle cells. Both PD98059 and U0126, inhibitors of the upstream activator of mitogen-activated protein kinase kinase, inhibited augmentation of endothelin-1 expression stimulated with leptin. Leptin induced significant tyrosine phosphorylation of epidermal growth factor receptor, which was significantly attenuated by two inhibitors, an epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of epidermal growth factor receptor transactivation induced by leptin is dependent on proteolytically released epidermal growth factor receptor ligands. Pretreatment of cells with AG1478 significantly reduced the degree of phosphorylation of extracellular signal-regulated kinase and endothelin-1 expression. Our results reveal that epidermal growth factor receptor transactivation is involved in the leptin signaling pathway in vascular smooth muscle cells, which may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects. PMID:17678888

  13. 20 years of leptin: leptin and reproduction: past milestones, present undertakings, and future endeavors.

    PubMed

    Chehab, Farid F

    2014-10-01

    The association between leptin and reproduction originated with the leptin-mediated correction of sterility in ob/ob mice and initiation of reproductive function in normal female mice. The uncovering of a central leptin pathway regulating food intake prompted the dissection of neuroendocrine mechanisms involving leptin in the metabolic control of reproduction. The absence of leptin receptors on GnRH neurons incited a search for intermediary neurons situated between leptin-responsive and GnRH neurons. This review addresses the most significant findings that have furthered our understanding of recent progress in this new field. The role of leptin in puberty was impacted by the discovery of neurons that co-express kisspeptin, neurokinin B, and dynorphin and these could act as leptin intermediates. Furthermore, the identification of first-order leptin-responsive neurons in the premammilary ventral nucleus and other brain regions opens new avenues to explore their relationship to GnRH neurons. Central to these advances is the unveiling that agouti-related protein/neuropeptide Y neurons project onto GnRH and kisspeptin neurons, allowing for a crosstalk between food intake and reproduction. Finally, while puberty is a state of leptin sensitivity, mid-gestation represents a state of leptin resistance aimed at building energy stores to sustain pregnancy and lactation. The mechanisms underlying leptin resistance in pregnancy have lagged; however, the establishment of this natural state is significant. Reproduction and energy balance are tightly controlled and backed up by redundant mechanisms that are critical for the survival of our species. It will be the goal of the following decade to shed new light on these complex and essential pathways.

  14. Breast Milk Hormones and Their Protective Effect on Obesity

    PubMed Central

    Savino, Francesco; Liguori, Stefania A.; Fissore, Maria F.; Oggero, Roberto

    2009-01-01

    Data accumulated over recent years have significantly advanced our understanding of growth factors, cytokines, and hormones in breast milk. Here we deal with leptin, adiponectin, IGF-I, ghrelin, and the more recently discovered hormones, obestatin, and resistin, which are present in breast milk and involved in food intake regulation and energy balance. Little is known about these compounds in infant milk formulas. Nutrition in infancy has been implicated in the long-term tendency to obesity, and a longer duration of breastfeeding appears to protect against its development. Diet-related differences in serum leptin and ghrelin values in infancy might explain anthropometric differences and differences in dietary habits between breast-fed and formula-fed infants also later in life. However, there are still gaps in our understanding of how hormones present in breast milk affect children. Here we examine the data related to hormones contained in mother's milk and their potential protective effect on subsequent obesity. PMID:20049153

  15. Impact of anthropometric measures and serum leptin on severity of gastroesophageal reflux disease.

    PubMed

    Abdelkader, N A; Montasser, I F; Bioumy, E E; Saad, W E

    2015-10-01

    The aim of this prospective study was to evaluate the impact of obesity, determined by different anthropometric measures, on clinical and endoscopic severity of GERD and the relation between serum leptin and clinical and endoscopic severity of GERD in Egyptian patients. The study was carried out at Ain Shams University Hospitals and Theodor Bilharz Research Institute, Cairo, Egypt. A total of 60 patients with clinically and endoscopically evident gastroesophageal reflux disease (GERD) were enrolled in this study as well as 20 healthy subjects matched for age and gender serving as the control group. Patients were divided according to their body mass index (BMI) into two groups: group 1 (n = 30): overweight and obese (BMI ≥ 25 and/or waist-to-height ratio [WHtR] ≥ 0.5) and group 2 (n = 30): normal weight (BMI ≥ 18 to < 25 and/or WHtR ≥ 0.4 to < 0.5). Upper gastrointestinal endoscopy, anthropometric measures, and symptom severity score questionnaire were done for all patients. Serum leptin hormone was assessed for patients and control groups.The evidence revealed statistically significant difference between the two groups in terms of different anthropometric measures (P < 0.00) except the height (P < 0.9), abdominal fat depot equations (P < 0.00), endoscopic findings according to Los Angeles classification (P < 0.001), symptom severity score (P < 0.00), and serum leptin hormone (43.96 ± 23.50 in group 1 vs. 7.5133 ± 8.18294 in group 2 and 6.98 ± 5.90 in the control group) (P = 0.00). Obesity in general and central (abdominal) obesity specifically has significant impact on clinical and endoscopic severity of GERD. Increased leptin hormone level is associated with clinical and endoscopic severity of GERD. Future trial on larger number of patients is emphasized.

  16. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults

    PubMed Central

    Baicy, Kate; London, Edythe D.; Monterosso, John; Wong, Ma-Li; Delibasi, Tuncay; Sharma, Anil; Licinio, Julio

    2007-01-01

    A missense mutation in the ob gene causes leptin deficiency and morbid obesity. Leptin replacement to three adults with this mutation normalized body weight and eating behavior. Because the neural circuits mediating these changes were unknown, we paired functional magnetic resonance imaging (fMRI) with presentation of food cues to these subjects. During viewing of food-related stimuli, leptin replacement reduced brain activation in regions linked to hunger (insula, parietal and temporal cortex) while enhancing activation in regions linked to inhibition and satiety (prefrontal cortex). Leptin appears to modulate feeding behavior through these circuits, suggesting therapeutic targets for human obesity. PMID:17986612

  17. Effect of leptin gene polymorphisms on growth, slaughter and meat quality traits of grazing Brangus steers.

    PubMed

    Corva, P M; Fernández Macedo, G V; Soria, L A; Papaleo Mazzucco, J; Motter, M; Villarreal, E L; Schor, A; Mezzadra, C A; Melucci, L M; Miquel, M C

    2009-01-01

    Leptin is a hormone that affects the regulation of feed intake, energy balance and body composition in mammals. Several polymorphisms in the bovine leptin gene have been associated with phenotypic variance of these traits. We evaluated two known single nucleotide polymorphisms (SNPs) in the leptin gene of 253 grazing Brangus steers. Brangus is a 5/8 Angus-3/8 Brahman composite. Data were collected during two consecutive growth/fattening cycles from two farms in southeast Buenos Aires province, Argentina. One of the markers is in the promoter region of the gene (SNP1) and the other is a non-synonymous polymorphism in exon 2 (SNP2). The traits that we evaluated were live weight gain in the spring, gain in backfat thickness in the spring, final live weight, final ultrasound backfat thickness, final ultrasound rib eye area, carcass weight and length, carcass yield, kidney fat, kidney fat percentage, backfat thickness, rib eye area, and intramuscular fat percentage. Both markers affected some meat traits; though the only significant associations were of SNP1 with ultrasound rib eye area and of SNP2 with carcass yield and backfat thickness. Under the same conditions as in the present study, leptin markers could be of help only as part of a larger genotyping panel including other relevant genes. PMID:19283678

  18. Impact of acute sleep restriction on cortisol and leptin levels in young women.

    PubMed

    Omisade, Antonina; Buxton, Orfeu M; Rusak, Benjamin

    2010-04-19

    Sleep restriction alters hormone patterns and appetite in men, but less is known about effects on women. We assessed effects of overnight sleep restriction on cortisol and leptin levels and on appetite in young women. Participants' baseline sleep duration and eating habits were monitored for a week before the study. Salivary cortisol and leptin were sampled from fifteen healthy women (aged 18-25) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline day) and then after a night including only 3h sleep (Post sleep-restriction day). Participants also completed appetite questionnaires on both days. Sleep restriction significantly reduced morning cortisol levels (p=0.02), elevated morning leptin levels (p=0.04), elevated afternoon/evening cortisol area under the curve values (p=0.008), and slowed the decline in cortisol concentration during the day (p=0.04). Hunger and craving scores did not differ significantly between days. A single night of restricted sleep affected cortisol rhythms and morning leptin levels in young women.

  19. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III).

    PubMed

    Asao, Keiko; Marekani, Amandine Sambira; VanCleave, Jessica; Rothberg, Amy E

    2016-02-25

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988-1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%-12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles.

  20. Relationship between bone mineral density, leptin and insulin concentration in Brazilian obese adolescents.

    PubMed

    do Prado, Wagner Luiz; de Piano, Aline; Lazaretti-Castro, Marise; de Mello, Marco Túlio; Stella, Sérgio Garcia; Tufik, Sergio; do Nascimento, Cláudia Maria Oller; Oyama, Lila Missae; Lofrano, Mara Cristina; Tock, Lian; Caranti, Danielle Arisa; Dâmaso, Ana Raimunda

    2009-01-01

    Despite the epidemic of adolescent obesity, the effect of obesity and hormones on bone mineral accrual during growth is poorly understood. Studies using dual-energy X-ray to examine the effect of obesity on bone mass in children and adolescents have yielded conflicting results. The aim of this study was to explore the combined and independent contributions of body mass index, body composition, leptin, insulin, glucose levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) to bone mineral density (BMD) and bone mineral content in a group of Brazilian obese adolescents. This study included 109 post-pubescent obese adolescents. A whole-body dual-energy X-ray absorptiometry scan was performed,using a HOLOGIC QDR4200, to determine whole-body BMD and body composition. Blood samples were collected in the outpatient clinic after an overnight fast, and evaluated for fasting blood glucose and immunoreactive insulin. Leptin levels were assessed with a radioimmunoassay kit. Insulin resistance was assessed by HOMA-IR and the quantitative insulin sensitivity check index. Our results showed that insulin levels and HOMA-IR correlated negatively with BMD and a linear regression analysis showed that serum leptin is inversely associated to BMD adjusted for body mass. In conclusion, our data support the hypothesis that leptin, insulin and HOMA-IR are inversely associated with BMD and play a significant direct role in bone metabolism. PMID:19466592

  1. Insulin receptor substrate 4 couples the leptin receptor to multiple signaling pathways.

    PubMed

    Wauman, Joris; De Smet, Anne-Sophie; Catteeuw, Dominiek; Belsham, Denise; Tavernier, Jan

    2008-04-01

    Leptin is an adipokine that regulates food intake and energy expenditure by activating its hypothalamic leptin receptor (LR). Members of the insulin receptor substrate (IRS) family serve as adaptor proteins in the signaling pathways of several cytokines and hormones and a role for IRS2 in central leptin physiology is well established. Using mammalian protein-protein interaction trap (MAPPIT), a cytokine receptor-based two-hybrid method, in the N38 hypothalamic cell line, we here demonstrate that also IRS4 interacts with the LR. This recruitment is leptin dependent and requires phosphorylation of the Y1077 motif of the LR. Domain mapping of IRS4 revealed the critical role of the pleckstrin homology domain for full interaction. In line with its function as an adaptor protein, IRS4 interacted with the regulatory p85 subunit of the phosphatidylinositol 3-kinase, phospholipase Cgamma, and the suppressor of cytokine signaling (SOCS) family members SOCS2, SOCS6, and SOCS7 and thus can modulate LR signaling. PMID:18165436

  2. Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding.

    PubMed

    Hsuchou, Hung; Wang, Yuping; Cornelissen-Guillaume, Germaine G; Kastin, Abba J; Jang, Eunjin; Halberg, Franz; Pan, Weihong

    2013-10-01

    Leptin, a hormone mainly produced by fat cells, shows cell-specific effects to regulate feeding and metabolic activities. We propose that an important feature of metabolic dysregulation resulting in obesity is the loss of the circadian rhythm of biopotentials. This was tested in the pan-leptin receptor knockout (POKO) mice newly generated in our laboratory. In the POKO mice, leptin no longer induced pSTAT-3 signaling after intracerebroventricular injection. Three basic phenotypes were observed: the heterozygotes had similar weight and adiposity as the wild-type (WT) mice (>60% of the mice); the homozygotes were either fatter (∼30%), or rarely leaner (<5%) than the WT mice. By early adulthood, the POKO mice had higher average body weight and adiposity than their respective same-sex WT littermate controls, and this was consistent among different batches. The homozygote fat POKO showed significant reduction of midline estimating statistic of rhythm of circadian parameters, and shifts of ultradian rhythms. The blunted circadian rhythm of these extremely obese POKO mice was also seen in their physical inactivity, longer feeding bouts, and higher food intake. The extent of obesity correlated with the blunted circadian amplitude, accumulative metabolic and locomotor activities, and the severity of hyperphagia. This contrasts with the heterozygote POKO mice which showed little obesity and metabolic disturbance, and only subtle changes of the circadian rhythm of metabolic activity without alterations in feeding behavior. The results provide a novel aspect of leptin resistance, almost manifesting as an "all or none" phenomenon.

  3. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III)

    PubMed Central

    Asao, Keiko; Marekani, Amandine Sambira; VanCleave, Jessica; Rothberg, Amy E.

    2016-01-01

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988–1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%–12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles. PMID:26927164

  4. Effect of leptin gene polymorphisms on growth, slaughter and meat quality traits of grazing Brangus steers.

    PubMed

    Corva, P M; Fernández Macedo, G V; Soria, L A; Papaleo Mazzucco, J; Motter, M; Villarreal, E L; Schor, A; Mezzadra, C A; Melucci, L M; Miquel, M C

    2009-02-03

    Leptin is a hormone that affects the regulation of feed intake, energy balance and body composition in mammals. Several polymorphisms in the bovine leptin gene have been associated with phenotypic variance of these traits. We evaluated two known single nucleotide polymorphisms (SNPs) in the leptin gene of 253 grazing Brangus steers. Brangus is a 5/8 Angus-3/8 Brahman composite. Data were collected during two consecutive growth/fattening cycles from two farms in southeast Buenos Aires province, Argentina. One of the markers is in the promoter region of the gene (SNP1) and the other is a non-synonymous polymorphism in exon 2 (SNP2). The traits that we evaluated were live weight gain in the spring, gain in backfat thickness in the spring, final live weight, final ultrasound backfat thickness, final ultrasound rib eye area, carcass weight and length, carcass yield, kidney fat, kidney fat percentage, backfat thickness, rib eye area, and intramuscular fat percentage. Both markers affected some meat traits; though the only significant associations were of SNP1 with ultrasound rib eye area and of SNP2 with carcass yield and backfat thickness. Under the same conditions as in the present study, leptin markers could be of help only as part of a larger genotyping panel including other relevant genes.

  5. Serum leptin concentrations during severe protein-energy malnutrition: correlation with growth parameters and endocrine function.

    PubMed

    Soliman, A T; ElZalabany, M M; Salama, M; Ansari, B M

    2000-07-01

    Circulating leptin, insulin, insulin-like growth factor-I (IGF-I), cortisol, and albumin concentrations and the growth hormone (GH) response to provocation were measured in 30 children with severe protein-energy malnutrition (PEM), 20 with marasmus and 10 with kwashiorkor, as well as 10 age-matched normal children (body mass index [BMI] >50th and <90th percentile for age and sex) and 10 prepubertal obese children (BMI >95th percentile for age and sex). Patients with PEM had a significantly lower BMI, midarm circumference (MAC), and skinfold thickness (SFT) compared with the age-matched control group. Basal cortisol and GH concentrations were significantly higher in the malnourished groups versus controls. Leptin and IGF-I were significantly lower in the marasmic and kwashiorkor groups versus normal children. Fasting insulin levels were significantly decreased in the kwashiorkor group compared with marasmic and normal children. The BMI correlated significantly with leptin (r = .77, P < .001), basal insulin (r = .61, P < .001), and IGF-I (r = .77, P < .001) and negatively with basal GH (r = -.52, P < .001). These findings suggest that during prolonged nutritional deprivation, the decreased energy intake, diminished subcutaneous fat mass, and declining insulin (and possibly IGF-I) concentration suppress leptin production. In support of this view, serum leptin levels were positively correlated with triceps, scapular, and abdominal SFT (r = .763, .75, and .744, respectively, P < .0001) in all of the children. Moreover, basal insulin and circulating IGF-I were correlated significantly with leptin concentrations (r = .47 and .62, respectively, P < .001). Basal levels of cortisol and GH were significantly elevated in the 2 groups with severe PEM. It is suggested that low leptin levels can stimulate the hypothalamic-pituitary-adrenal (HPA) axis and possibly the hypothalamic-pituitary-GH axis to maintain the high cortisol and GH levels necessary for effective lipolysis to

  6. New insights in leptin resistance mechanisms in mice.

    PubMed

    Balland, Eglantine; Cowley, Michael A

    2015-10-01

    Leptin resistance is one of the main challenges of obesity. To date, two levels of resistance have been identified, first a decreased rate of leptin uptake into the brain and secondly a diminished central response to leptin. New findings have identified the mechanisms of leptin transport and demonstrated that it can be rescued in obesity, but it did not overcome the problem of central resistance. Alteration in the actions of leptin following diet-induced obesity (DIO) appears to be a multifactorial condition. Several phosphatases are inhibiting leptin signaling pathways in a pathological way. Besides, hypothalamic inflammation alters the neuronal circuits that control metabolism. Recent studies describing both mechanisms (inhibition of leptin signaling and inflammation), have provided key insights to potential new targets for treatment. However, recent data showing that DIO mice may conserve a cellular and physiological response to endogenous leptin, highlights the need to redefine the concept of "leptin resistance".

  7. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    SciTech Connect

    Hamrick, Mark W.; Herberg, Samuel; Arounleut, Phonepasong; He, Hong-Zhi; Shiver, Austin; Qi, Rui-Qun; Zhou, Li; Isales, Carlos M.; and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  8. Genetics Home Reference: leptin receptor deficiency

    MedlinePlus

    ... leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998 Mar 26;392(6674):398-401. Citation ... and human weight regulation: lessons from experiments of nature. Ann Acad Med Singapore. 2009 Jan;38(1): ...

  9. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century.

    PubMed

    Blüher, Matthias; Mantzoros, Christos S

    2015-01-01

    This year marks the 20th anniversary of the discovery of leptin, which has tremendously stimulated translational obesity research. The discovery of leptin has led to realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant leptin and the leptin analog metreleptin are already available for the treatment of congenital leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity but also other disease states associated with and influenced by adipose tissue size and activity. In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action

  10. The expression of leptin receptor in the ovary of the queen: leptin receptor expression in queen ovary.

    PubMed

    Albrizio, M; Roscino, M T; Trisolini, C; Binetti, F; Rizzo, A; Sciorsci, R L

    2013-10-01

    Leptin is a Ob gene product secreted mainly by adipose tissue. Several reports showed leptin production by other tissue including the ovary. The action of leptin is mediated upon binding to its receptor widely expressed in reproductive tissues in different species. In fact, there are growing evidences that leptin plays an important role in the modulation of reproductive functions. Therefore, the aim of this study was to evaluate in the queen, the expression of leptin receptor during the functional ovarian cycle and pregnancy. We found that the ovaries of the queen express leptin receptor in all the examined phases. The highest leptin receptor expression was found in the luteal phase (pseudopregnancy, pregnancy) compared to other phases of the cycle (anestrus, proestrus, estrus). The variations in the expression of leptin receptor suggest a likely implication of leptin in the modulation of ovarian activity, in the examined species.

  11. Obesity is associated with increased seminal insulin and leptin alongside reduced fertility parameters in a controlled male cohort

    PubMed Central

    2014-01-01

    Background Obesity appears to be associated with male reproductive dysfunction and infertility, although this has been inconsistent and inconclusive. Insulin and leptin are known mediators and modulators of the hypothalamus-pituitary-testes axis, contributing to the regulation of male reproductive potential and overall wellbeing. These hormones are also present in semen influencing sperm functions. Although abdominal obesity is closely associated with insulin resistance (hyperinsulinaemia), hyperleptinaemia and glucose dysfunction, changes in seminal plasma concentrations of insulin, leptin and glucose in obese males has not previously been investigated. Methods This small case controlled study assessed serum and seminal concentrations of insulin, leptin and glucose in obese (BMI > =30; n = 23) and non-obese (BMI < 30; n = 19) males. Following a detailed medical history and examination, participants meeting the inclusion criteria were entered for data analysis. Body parameters such as BMI, waist and hip circumference and the waist hip ratio were measured. Serum and semen samples were collected and assayed for insulin, leptin and glucose. Semen samples also underwent a standard semen analysis, with sperm mitochondrial membrane potential (MMP) and DNA fragmentation (DF). Results Obesity was associated with increased serum and seminal insulin and leptin, with no significant difference in seminal glucose. Serum and seminal concentrations of insulin and leptin were positively correlated. Furthermore, obesity was associated with decreased sperm concentration, sperm vitality and increased MMP and DF, with a non-significant impact on motility and morphology. Conclusions Hyperinsulinaemia and hyperleptinaemia are associated with increased seminal insulin and leptin concentrations, which may negatively impact male reproductive function in obesity. Insulin was also found to be highly concentrated in the seminal plasma of both groups. This data will contribute

  12. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism.

    PubMed

    Scherer, Thomas; Buettner, Christoph

    2011-09-01

    Fatty acids released from white adipose tissue (WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes. PMID:21713385

  13. Leptin and leptin receptor are detectable in equine spermatozoa but are not involved in in vitro fertilisation.

    PubMed

    Lange-Consiglio, Anna; Corradetti, Bruna; Perrini, Claudia; Bizzaro, Davide; Cremonesi, Fausto

    2016-04-01

    In human and swine, leptin (OB) has been identified in seminal plasma and leptin receptors (OB-R) on the cell surface of spermatozoa, indicating that spermatozoa are a target for OB. This hormone has also been detected in follicular fluid (FF) in women and mares, although its role requires further study. The aims of this study were to investigate the immunolocalisation and the expression of OB and OB-R in equine spermatozoa and to evaluate the involvement of OB in equine in vitro fertilisation (IVF). Since progesterone (P) and OB are both found in FF, the individual and combined effects of these two hormones were studied in equine IVF and compared with the results obtained from the use of FF for in vitro sperm preparation. For the first time, we were able to identify OB and OB-R mRNA and their corresponding proteins in equine spermatozoa. When spermatozoa were treated with OB, there was a decrease in the three motility parameters VSL, STR and LIN, commonly associated with hyperactivation, whilst the acrosome reaction rate increased (P<0.05). The fertilisation rate was 51% with FF, 46.15% with P, 43.64% with P+OB and 0% with OB alone. The percentage of eight-cell stage embryos was 18.7% with FF, 17.1% with P and 16.7% with OB+P. OB alone did not permit oocyte fertilisation, indicating that, in the horse, OB is involved in capacitation and hyperactivation but not in sperm penetration.

  14. Interaction between energy homeostasis and reproduction: central effects of leptin and ghrelin on the reproductive axis.

    PubMed

    Tena-Sempere, M

    2013-12-01

    Reproductive maturation and function are sensitive to the metabolic state of the organism and the magnitude of body fuel reserves; hence, conditions ranging from energy insufficiency to morbid obesity impact the timing of puberty and are frequently linked to fertility problems. This phenomenon is the result of the close interplay between a diversity of nutritional cues and metabolic signals (including hormones) with different elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will focus our attention on the 'reproductive' roles of 2 key metabolic hormones, namely, the adipose signal, leptin, and the gut hormone, ghrelin. These 2 factors, which have been proposed to operate as functional antagonists in the control of metabolism and energy homeostasis, are also provided with important, and in many cases opposite, roles in the regulation of puberty onset and gonadal function. We will provide herein an update view of the reproductive effects of leptin and ghrelin, with a major emphasis on the actions of these 2 key hormones upon the central elements of the HPG axis, including their putative effects on Kiss1 and other reproductive neuronal networks. This will help to understand the mechanisms whereby reproductive function is gated and dynamically regulated by metabolic signals at different key developmental stages, such as puberty and adulthood.

  15. Higher habitual intake of dietary fat and carbohydrates are associated with lower leptin and higher ghrelin concentrations in overweight and obese postmenopausal women with elevated insulin levels.

    PubMed

    Kong, Angela; Neuhouser, Marian L; Xiao, Liren; Ulrich, Cornelia M; McTiernan, Anne; Foster-Schubert, Karen E

    2009-11-01

    A highly regulated homeostatic system governs body weight; however, it is possible that this system might be impaired by the sustained intake of highly palatable foods. Short-term feeding studies suggest that the appetite-stimulating hormone ghrelin is suppressed less effectively by dietary fat intake, and diets high in sucrose decrease levels of the adipose hormone leptin. We hypothesized that higher habitual intake of dietary fat and carbohydrate (CHO) would be associated with elevated concentrations of circulating plasma ghrelin and lower circulating leptin in humans, a hormonal profile that could promote weight gain. To test our hypothesis, we examined the cross-sectional associations of ghrelin and leptin with the habitual macronutrient intake of 165 healthy overweight and obese sedentary women and tested the modifying role of insulin in these associations. We observed a significant inverse association between leptin concentrations and percentage energy from CHO independent of body mass index, percentage body fat, age, and intraabdominal fat (beta = -0.11 P = .04). No significant associations were observed between ghrelin and macronutrients or their subtypes among the total cohort. Among women with insulin concentrations at or greater than the median, we found a statistically significant positive association between intake of saturated fat and ghrelin concentrations, as well as additional statistically significant associations between leptin concentrations and macronutrients not observed among the total cohort. Our results provide some evidence that diets higher in fat and CHO are associated with a hormonal profile (ie, lower leptin and higher ghrelin concentrations), which could enhance weight gain, particularly among individuals with higher circulating insulin concentrations.

  16. Omega-3 fatty acids: a review of the effects on adiponectin and leptin and potential implications for obesity management.

    PubMed

    Gray, B; Steyn, F; Davies, P S W; Vitetta, L

    2013-12-01

    An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adiponectin and leptin. The marked change in circulating concentrations of these hormones in obesity has been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects. This may pose benefits in the prevention of weight regain in these subjects following calorie restriction.

  17. Identification of a soluble leptin receptor in crucian carp with different binding affinity to leptin-a and leptin-b.

    PubMed

    Xie, Feifei; Li, Xin; Huang, Saifan; Li, Jiyuan; Guo, Xiaopin; Cao, Yibin

    2016-01-01

    Soluble leptin receptor (sLepR) is the main leptin-binding protein in plasma and contributes to activation of circulating leptin. In this study, we identified a sLepR in plasma of crucian carp (Carassius carassius) using a pull-down assay, and the interaction of sLepR with its ligand is confirmed by a cross-linking study. In addition, we found that leptin-a has higher affinity than leptin-b for sLepR. According to our knowledge, this is the first experimental report about the main ligand of sLepR in teleost.

  18. Palmitate-induced Endoplasmic Reticulum stress and subsequent C/EBPα Homologous Protein activation attenuates leptin and Insulin-like growth factor 1 expression in the brain.

    PubMed

    Marwarha, Gurdeep; Claycombe, Kate; Schommer, Jared; Collins, David; Ghribi, Othman

    2016-11-01

    The peptide hormones Insulin-like growth factor-1 (IGF1) and leptin mediate a myriad of biological effects - both in the peripheral and central nervous systems. The transcription of these two hormones is regulated by the transcription factor C/EBPα, which in turn is negatively regulated by the transcription factor C/EBP Homologous Protein (CHOP), a specific marker of endoplasmic reticulum (ER) stress. In the peripheral system, disturbances in leptin and IGF-1 levels are implicated in a variety of metabolic diseases including obesity, diabetes, atherosclerosis and cardiovascular diseases. Current research suggests a positive correlation between consumption of diets rich in saturated free fatty acids (sFFA) and metabolic diseases. Induction of ER stress and subsequent dysregulation in the expression levels of leptin and IGF-1 have been shown to mediate sFFA-induced metabolic diseases in the peripheral system. Palmitic acid (palmitate), the most commonly consumed sFFA, has been shown to be up-taken by the brain, where it may promote neurodegeneration. However, the extent to which palmitate induces ER stress in the brain and attenuates leptin and IGF1 expression has not been determined. We fed C57BL/6J mice a palmitate-enriched diet and determined effects on the expression levels of leptin and IGF1 in the hippocampus and cortex. We further determined the extent to which ER stress and subsequent CHOP activation mediate the palmitate effects on the transcription of leptin and IGF1. We demonstrate that palmitate induces ER stress and decreases leptin and IGF1 expression by inducing the expression of CHOP. The molecular chaperone 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress, precludes the palmitate-evoked down-regulation of leptin and IGF1 expression. Furthermore, the activation of CHOP in response to ER stress is pivotal in the attenuation of leptin and IGF1 expression as knocking-down CHOP in mice or in SH-SY5Y and Neuro-2a (N2a) cells rescues the palmitate

  19. Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress.

    PubMed

    Hosoi, Toru; Yamaguchi, Rie; Noji, Kikuko; Matsuo, Suguru; Baba, Sachiko; Toyoda, Keisuke; Suezawa, Takahiro; Kayano, Takaaki; Tanaka, Shinpei; Ozawa, Koichiro

    2014-03-01

    Endoplasmic reticulum (ER) stress, caused by the accumulation of unfolded proteins, is involved in the development of obesity. We demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited chaperone activity, which reduced protein aggregation and alleviated ER stress-induced leptin resistance, characterized by insensitivity to the actions of the anti-obesity hormone leptin. This result was further supported by flurbiprofen attenuating high-fat diet-induced obesity in mice. The other NSAIDs tested did not exhibit such effects, which suggested that this anti-obesity action is mediated independent of NSAIDs. Using ferriteglycidyl methacrylate beads, we identified aldehyde dehydrogenase as the target of flurbiprofen, but not of the other NSAIDs. These results suggest that flurbiprofen may have unique pharmacological properties that reduce the accumulation of unfolded proteins and may represent a new class of drug for the fundamental treatment of obesity.

  20. Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress

    PubMed Central

    Hosoi, Toru; Yamaguchi, Rie; Noji, Kikuko; Matsuo, Suguru; Baba, Sachiko; Toyoda, Keisuke; Suezawa, Takahiro; Kayano, Takaaki; Tanaka, Shinpei; Ozawa, Koichiro

    2014-01-01

    Endoplasmic reticulum (ER) stress, caused by the accumulation of unfolded proteins, is involved in the development of obesity. We demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited chaperone activity, which reduced protein aggregation and alleviated ER stress-induced leptin resistance, characterized by insensitivity to the actions of the anti-obesity hormone leptin. This result was further supported by flurbiprofen attenuating high-fat diet-induced obesity in mice. The other NSAIDs tested did not exhibit such effects, which suggested that this anti-obesity action is mediated independent of NSAIDs. Using ferriteglycidyl methacrylate beads, we identified aldehyde dehydrogenase as the target of flurbiprofen, but not of the other NSAIDs. These results suggest that flurbiprofen may have unique pharmacological properties that reduce the accumulation of unfolded proteins and may represent a new class of drug for the fundamental treatment of obesity. Subject Categories Metabolism; Pharmacology & Drug Discovery PMID:24421337

  1. Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses

    PubMed Central

    Bonnavion, Patricia; Jackson, Alexander C.; Carter, Matthew E.; de Lecea, Luis

    2015-01-01

    The hypothalamic–pituitary–adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA axis are poorly understood. Here using optogenetic approaches in mice, we show that neurons that produce hypocretin (Hcrt)/orexin in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviours and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses. PMID:25695914

  2. Selective Leptin Insensitivity and Alterations in Female-Reproductive Patterns Linked to Hyperleptinemia during Infancy

    PubMed Central

    Schroeder, Mariana; Kronfeld-Schor, Noga; Weller, Aron

    2013-01-01

    The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK1 deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health. PMID:23544111

  3. Serum leptin and insulin levels in lactating protein-restricted rats: implications for energy balance.

    PubMed

    Ferreira, C L P; Macêdo, G M; Latorraca, M Q; Arantes, V C; Veloso, R V; Carneiro, E M; Boschero, A C; Nascimento, C M O; Gaíva, M H

    2007-01-01

    The present study analysed the effect of protein restriction on serum insulin and leptin levels and their relationship with energy balance during lactation. Four groups of rats received isocaloric diets containing 170 g protein/kg or 60 g protein/kg from pregnancy until the 14th day of lactation: control non-lactating, control lactating (both fed a control diet), low-protein non-lactating and low-protein lactating. Energy intake, body composition, energy balance, serum insulin and leptin concentrations and the relationship between these hormones and several factors related to obesity were analysed. Low-protein-intake lactating rats exhibited hypoinsulinaemia, hyperleptinaemia, hypophagia and decreased energy expenditure compared with control lactating rats. The protein level in the carcasses was lower in the low-protein lactating group than in the control lactating group, resulting in a higher fat content in the first group compared with the latter. Body fat correlated inversely with serum insulin and positively with serum leptin level. There was a significant negative correlation between serum leptin and energy intake, and a positive relationship between energy intake and serum insulin level in lactating rats and in the combined data from both groups. Energy expenditure was correlated positively with serum insulin and negatively with serum leptin in lactating rats and when data from control non-lactating and lactating rats were pooled. Lactating rats submitted to protein restriction, compared with lactating control rats, showed that maternal reserves were preserved owing to less severe negative energy balance. This metabolic adaptation was obtained, at least in part, by hypoinsulinaemia that resulted in increased insulin sensitivity favouring enhanced fat deposition, hyperleptinaemia and hypophagia. PMID:17217557

  4. Leptin and Hunger Levels in Young Healthy Adults After One Night of Sleep Loss

    PubMed Central

    Pejovic, Slobodanka; Vgontzas, Alexandros N.; Basta, Maria; Tsaoussoglou, Marina; Zoumakis, Emanuel; Vgontzas, Angeliki; Bixler, Edward O.; Chrousos, George P.

    2013-01-01

    Summary Short-term sleep curtailment associated with activation of the stress system in healthy, young adults has been shown to be associated with decreased leptin levels, impaired insulin sensitivity and increased hunger and appetite. To assess the effects of one night of sleep loss in a less stressful environment on hunger, leptin, adiponectin, cortisol, and blood pressure/heart rate and whether a 2-hour mid-afternoon nap reverses the changes associated with sleep loss, 21 young healthy individuals (10 men, 11 women) participated in a 7-day sleep deprivation experiment (4 consecutive nights followed by a night of sleep loss and 2 recovery nights). Half of the subjects were randomly assigned to take a mid-afternoon nap (1400–1600) the day following the night of total sleep loss. Serial 24-hour blood sampling and hunger scales were completed on the fourth (pre-deprivation) and sixth day (post-deprivation). Leptin levels were significantly increased after one night of total sleep loss, whereas adiponectin, cortisol levels, blood pressure/heart rate, and hunger were not affected. Daytime napping did not influence the effects of sleep loss on leptin, adiponectin or hunger. Acute sleep loss, in a less stressful environment, influences leptin levels in an opposite manner from that of short-term sleep curtailment associated with activation of the stress system. It appears that sleep loss associated with activation of the stress system but not sleep loss per se may lead to increased hunger and appetite and hormonal changes which ultimately may lead to increased consumption of “comfort” food and obesity. PMID:20545838

  5. The effects of long-term leptin administration on morphometrical changes of mice testicular tissue

    PubMed Central

    Esmaili-Nejad, Mohammad-Reza; Babaei, Homayoon; Kheirandish, Reza

    2015-01-01

    Objective(s): Leptin is a novel and interesting hormone for anyone trying to lose weight, but its effects on male gonad structure in longitudinal study is unknown. The present study was designed to explore morphometrical changes of mouse testicular tissue after long-term administration of leptin. Materials and Methods: Thirty healthy mature male mice were randomly assigned to either control (n=15) or treatment (n=15) groups. Leptin was intraperitoneally injected to the treatment group (0.1 µg/100 µl of physiological saline) once a day for 30 consecutive days, and control animals received normal saline with the same volume and route. Five mice from each experimental group were sacrificed at 15, 30 and 60 days after the beginning of treatments. Left testes were removed, weighted and then fixed in 10% buffered formalin, and stained with hematoxylin and eosine for morphometrical assays. Results: Except for sertoli cell nucleus diameter, which was affected from 30th day, evaluation of other morphometrical parameters such as Johnsen’s score, meiotic index, spermatogenesis, epithelial height, seminiferous tubules diameter and spermatogonial nucleus diameter revealed significant decrease from 15th day after leptin administration compare to those of the control group (P<0.05). Thus, meiotic index and spermatogonial cell nucleus diameter were two parameters that were further disturbed on 30th day compare to the day 15 (3.09±0.03 vs. 3.23±0.03, P=0.006 and 5.50±0.09 vs. 6.08±0.14, P=0.007, respectively). Conclusion: Our results showed that long-term administration of leptin could disturb testicular tissue structure and delay spermatogenesis process. PMID:26877846

  6. Leptin regulates bone formation via the sympathetic nervous system

    NASA Technical Reports Server (NTRS)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  7. Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin.

    PubMed

    Drew, Janice E

    2012-02-01

    Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have

  8. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding.

    PubMed

    Kim, Jae Geun; Suyama, Shigetomo; Koch, Marco; Jin, Sungho; Argente-Arizon, Pilar; Argente, Jesús; Liu, Zhong-Wu; Zimmer, Marcelo R; Jeong, Jin Kwon; Szigeti-Buck, Klara; Gao, Yuanqing; Garcia-Caceres, Cristina; Yi, Chun-Xia; Salmaso, Natalina; Vaccarino, Flora M; Chowen, Julie; Diano, Sabrina; Dietrich, Marcelo O; Tschöp, Matthias H; Horvath, Tamas L

    2014-07-01

    We found that leptin receptors were expressed in hypothalamic astrocytes and that their conditional deletion led to altered glial morphology and synaptic inputs onto hypothalamic neurons involved in feeding control. Leptin-regulated feeding was diminished, whereas feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data reveal an active role of glial cells in hypothalamic synaptic remodeling and control of feeding by leptin.

  9. The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells

    PubMed Central

    Maymó, Julieta Lorena; Pérez Pérez, Antonio; Maskin, Bernardo; Dueñas, José Luis; Calvo, Juan Carlos; Sánchez Margalet, Víctor; Varone, Cecilia Laura

    2012-01-01

    Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)2cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the

  10. Enhanced activity of hormone sensitive lipase (HSL) in mesenteric but not epididymal fat correlates with higher production of epinephrine in mesenteric adipocytes in rat model of cachectic rheumatoid arthritis.

    PubMed

    Stofkova, Andrea; Krskova, Katarina; Vaculin, Simon; Jurcovicova, Jana

    2016-06-01

    norepinephrine and epinephrine were increased in AA compared with both groups of controls. In eWAT adipocytes, AA but not pair feeding, upregulated norepinephrine levels. In mWAT adipocytes, AA rats showed higher epinephrine levels than pair-fed controls. Leptin levels in both WATs were depleted in AA animals in accordance with body weight loss. None of the measured cytokines in eWAT and mWAT was enhanced. Our results demonstrate augmented lipolytic activity in mWAT and not eWAT during cachectic arthritis. The adipocyte-derived cytokines do not seem to contribute to activated lipolysis. We first demonstrated enhanced presence of norepinephrine in perinodal adipocytes that may contribute to the regulation of local lipolytic activity by auto/paracrine fashion and thus provide independent fuel supply to activated lymph nodes.

  11. Hypothalamic PKA regulates leptin sensitivity and adiposity

    PubMed Central

    Yang, Linghai; McKnight, G. Stanley

    2015-01-01

    Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ–PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ–PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin. PMID:26381935

  12. Renaissance of leptin for obesity therapy.

    PubMed

    Quarta, Carmelo; Sánchez-Garrido, Miguel A; Tschöp, Matthias H; Clemmensen, Christoffer

    2016-05-01

    Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

  13. A novel unidirectional cross-talk from the insulin-like growth factor-I receptor to leptin receptor in human breast cancer cells.

    PubMed

    Ozbay, Tuba; Nahta, Rita

    2008-06-01

    Obesity is a major risk factor for the development and progression of breast cancer. Increased circulating levels of the obesity-associated hormones leptin and insulin-like growth factor-I (IGF-I) and overexpression of the leptin receptor (Ob-R) and IGF-I receptor (IGF-IR) have been detected in a majority of breast cancer cases and during obesity. Due to correlations between increased leptin, Ob-R, IGF-I, and IGF-IR in breast cancer, we hypothesized that molecular interactions may exist between these two signaling pathways. Coimmunoprecipitation and immunoblotting showed that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross-signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results show, for the first time, a novel interaction and cross-talk between the IGF-I and leptin receptors in human breast cancer cells.

  14. Mapping of the leptin binding sites and design of a leptin antagonist.

    PubMed

    Peelman, Frank; Van Beneden, Katrien; Zabeau, Lennart; Iserentant, Hannes; Ulrichts, Peter; Defeau, Delphine; Verhee, Annick; Catteeuw, Dominiek; Elewaut, Dirk; Tavernier, Jan

    2004-09-24

    The leptin/leptin receptor system shows strong similarities to the long-chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor cytokine/receptor systems. The IL-6 family cytokines interact with their receptors through three different binding sites I-III. The leptin structure was superposed on the crystal structures of several long-chain cytokines, and a series of leptin mutants was generated focusing on binding sites I-III. The effect of the mutations on leptin receptor (LR) signaling and on binding to the membrane proximal cytokine receptor homology domain (CRH2) of the LR was determined. Mutations in binding site I at the C terminus of helix D show a modest effect on signaling and do not affect binding to CRH2. Binding site II is composed of residues at the surface of helices A and C. Mutations in this site impair binding to CRH2 but have only limited effect on signaling. Site III mutations around the N terminus of helix D impair receptor activation without affecting binding to CRH2. We identified an S120A/T121A mutant in binding site III, which lacks any signaling capacity, but which still binds to CRH2 with wild type affinity. This leptin mutant behaves as a potent leptin antagonist both in vitro and in vivo. PMID:15213225

  15. The Impact of Leptin on Perinatal Development and Psychopathology

    PubMed Central

    Valleau, Jeanette C.; Sullivan, Elinor L.

    2014-01-01

    Leptin has long been associated with metabolism as it is a critical regulator of both food intake and energy expenditure, but recently, leptin dysregulation has been proposed as a mechanism of psychopathology. This review discusses the evidence supporting a role for leptin in mental health disorders and describes potential mechanisms that may underlie this association. Leptin plays a critical role in pregnancy and in fetal growth and development. Leptin’s role and profile during development is examined in available human studies and the validity of applying studies conducted in animal models to the human population are discussed. Rodents experience a postnatal leptin surge, which does not occur in humans or larger animal models. This suggests that further research using large mammal models, which have a leptin profile across pregnancy and development similar to humans, are of high importance. Maternal obesity and hyperleptinemia correlate with increased leptin levels in the umbilical cord, placenta, and fetus. Leptin levels are thought to impact fetal brain development; likely by activating proinflammatory cytokines that are known to impact many of the neurotransmitter systems that regulate behavior. Leptin is likely involved in behavioral regulation as leptin receptors are widely distributed in the brain, and leptin influences cortisol release, the mesoaccumbens dopamine pathway, serotonin synthesis, and hippocampal synaptic plasticity. In humans, both high and low levels of leptin are reported to be associated with psychopathology. This inconsistency is likely due to differences in the metabolic state of the study populations. Leptin resistance, which occurs in the obese state, may explain how both high and low levels of leptin are associated with psychopathology, as well as the comorbidity of obesity with numerous mental illnesses. Leptin resistance is likely to influence disorders such as depression and anxiety where both high and low leptin levels have been

  16. Transcriptional Characterization of Porcine Leptin and Leptin Receptor Genes

    PubMed Central

    Pérez-Montarelo, Dafne; Fernández, Almudena; Barragán, Carmen; Noguera, Jose L.; Folch, Josep M.; Rodríguez, M. Carmen; Óvilo, Cristina; Silió, Luis; Fernández, Ana I.

    2013-01-01

    The leptin (LEP) and its receptor (LEPR) regulate food intake and energy balance through hypothalamic signaling. However, the LEP-LEPR axis seems to be more complex and its expression regulation has not been well described. In pigs, LEP and LEPR genes have been widely studied due to their relevance. Previous studies reported significant effects of SNPs located in both genes on growth and fatness traits. The aim of this study was to determine the expression profiles of LEP and LEPR across hypothalamic, adipose, hepatic and muscle tissues in Iberian x Landrace backcrossed pigs and to analyze the effects of gene variants on transcript abundance. To our knowledge, non porcine LEPR isoforms have been described rather than LEPRb. A short porcine LEPR isoform (LEPRa), that encodes a protein lacking the intracellular residues responsible of signal transduction, has been identified for the first time. The LEPRb isoform was only quantifiable in hypothalamus while LEPRa appeared widely expressed across tissues, but at higher levels in liver, suggesting that both isoforms would develop different roles. The unique LEP transcript showed expression in backfat and muscle. The effects of gene variants on transcript expression revealed interesting results. The LEPRc.1987C>T polymorphism showed opposite effects on LEPRb and LEPRa hypothalamic expression. In addition, one out of the 16 polymorphisms identified in the LEPR promoter region revealed high differential expression in hepatic LEPRa. These results suggest a LEPR isoform-specific regulation at tissue level. Conversely, non-differential expression of LEP conditional on the analyzed polymorphisms could be detected, indicating that its regulation is likely affected by other mechanisms rather than gene sequence variants. The present study has allowed a transcriptional characterization of LEP and LEPR isoforms on a range of tissues. Their expression patterns seem to indicate that both molecules develop peripheral roles apart from

  17. Transcriptional Characterization of Porcine Leptin and Leptin Receptor Genes.

    PubMed

    Pérez-Montarelo, Dafne; Fernández, Almudena; Barragán, Carmen; Noguera, Jose L; Folch, Josep M; Rodríguez, M Carmen; Ovilo, Cristina; Silió, Luis; Fernández, Ana I

    2013-01-01

    The leptin (LEP) and its receptor (LEPR) regulate food intake and energy balance through hypothalamic signaling. However, the LEP-LEPR axis seems to be more complex and its expression regulation has not been well described. In pigs, LEP and LEPR genes have been widely studied due to their relevance. Previous studies reported significant effects of SNPs located in both genes on growth and fatness traits. The aim of this study was to determine the expression profiles of LEP and LEPR across hypothalamic, adipose, hepatic and muscle tissues in Iberian x Landrace backcrossed pigs and to analyze the effects of gene variants on transcript abundance. To our knowledge, non porcine LEPR isoforms have been described rather than LEPRb. A short porcine LEPR isoform (LEPRa), that encodes a protein lacking the intracellular residues responsible of signal transduction, has been identified for the first time. The LEPRb isoform was only quantifiable in hypothalamus while LEPRa appeared widely expressed across tissues, but at higher levels in liver, suggesting that both isoforms would develop different roles. The unique LEP transcript showed expression in backfat and muscle. The effects of gene variants on transcript expression revealed interesting results. The LEPRc.1987C>T polymorphism showed opposite effects on LEPRb and LEPRa hypothalamic expression. In addition, one out of the 16 polymorphisms identified in the LEPR promoter region revealed high differential expression in hepatic LEPRa. These results suggest a LEPR isoform-specific regulation at tissue level. Conversely, non-differential expression of LEP conditional on the analyzed polymorphisms could be detected, indicating that its regulation is likely affected by other mechanisms rather than gene sequence variants. The present study has allowed a transcriptional characterization of LEP and LEPR isoforms on a range of tissues. Their expression patterns seem to indicate that both molecules develop peripheral roles apart from

  18. Leptin gene transfer regulates fibromuscular development and lipid deposition in muscles via SIRT1, FOXO3a and PGC-1α in mice in vivo.

    PubMed

    Wang, Yi-Zhen; Huang, Yan-Na; Sun, Kai-Yue; Qi, Jian-Hua; Xiang, Lan

    2011-10-01

    Leptin gene transfer in the liver by hydrodynamic-based gene delivery instead of peptide administration was used to investigate the effects of leptin on muscle mass accretion and lipid accumulation in muscles of wild-type mice. Food intake (P<0.01), body weight (P<0.01) and white adipose tissue (P<0.01) were significantly reduced in the leptin gene-treated group compared with the control group. Moreover, plasma leptin concentration was significantly increased after administration of the mouse leptin gene at a dose of 15 µg per mouse for 1 day (P<0.01) or 1 week (P<0.05). Furthermore, the mRNA abundance of myosin heavy chain type I (MyHC-I), myosin heavy chain type II (MyHC-IIa, MyHC-IIx), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) genes in gastrocnemius muscle and extensor digitorum longus after administration of leptin for 1 week were significantly increased compared with the control group. Finally, we investigated the mechanism by which leptin gene transfer affects fibromuscular and fat deposition in muscle. Gene expression and protein levels of SIRT1, and proliferator-activated receptor-γ coactivator-1α (PGC-1α) were remarkably increased in extensor digitorum longus. On the other hand, PGC-1α and FOXO3a gene expression was observed to have significantly increased in gastrocnemius muscle. However, only changes in the protein levels of PGC-1α were observed (P<0.05). These results suggest that leptin may affect the growth and development of muscle, and fat deposition in wild-type mice via SIRT1 and FOXO3a and their downstream targets, including PGC-1α.

  19. Leptin receptors in human skeletal muscle.

    PubMed

    Guerra, Borja; Santana, Alfredo; Fuentes, Teresa; Delgado-Guerra, Safira; Cabrera-Socorro, Alfredo; Dorado, Cecilia; Calbet, Jose A L

    2007-05-01

    Human skeletal muscle expresses leptin receptor mRNA; however, it remains unknown whether leptin receptors (OB-R) are also expressed at the protein level. Fourteen healthy men (age = 33.1 +/- 2.0 yr, height = 175.9 +/- 1.7 cm, body mass = 81.2 +/- 3.8 kg, body fat = 22.5 +/- 1.9%; means +/- SE) participated in this investigation. The expression of OB-R protein was determined in skeletal muscle, subcutaneous adipose tissue, and hypothalamus using a polyclonal rabbit anti-human leptin receptor. Three bands with a molecular mass close to 170, 128, and 98 kDa were identified by Western blot with the anti-OB-R antibody. All three bands were identified in skeletal muscle: the 98-kDa and 170-kDa bands were detected in hypothalamus, and the 98-kDa and 128-kDa bands were detected in thigh subcutaneous adipose tissue. The 128-kDa isoform was not detected in four subjects, whereas in the rest its occurrence was fully explained by the presence of intermuscular adipose tissue, as demonstrated using an anti-perilipin A antibody. No relationship was observed between the basal concentration of leptin in serum and the 170-kDa band density. In conclusion, a long isoform of the leptin receptor with a molecular mass close to 170 kDa is expressed at the protein level in human skeletal muscle. The amount of 170-kDa protein appears to be independent of the basal concentration of leptin in serum.

  20. Dietary intake and ghrelin and leptin changes after sleeve gastrectomy

    PubMed Central

    Zavadilová, Vladislava; Holéczy, Pavol; Švagera, Zdeněk; Švorc, Pavol; Foltys, Aleš; Zonča, Pavel

    2014-01-01

    Introduction Surgical intervention in obesity is today the most effective treatment method in high level obesity management. Bariatric interventions not only ensure body weight reduction, but may influence dietary habits. Aim To assess changes in adipose hormones and dietary habits in obese patients after sleeve gastrectomy. Material and methods The study set comprised 37 subjects (29 females and 8 males) 24 to 68 years old with body mass index 43.0 ±4.9 kg/m2. Pre-operative examination included baseline measurements of body composition. Dietary habits and intake frequency were monitored by a questionnaire method. Follow-up examinations were carried out in a scope identical to the pre-operative examination, 6 and 12 months after surgery, respectively. Results The average patient weight loss 12 months after surgery was 31.7 kg. Excess weight loss was 55.2 ±20.6%. Patients reported reduced appetite (p < 0.001), increasingly regular food intake (p < 0.001), intake of more meal portions per day (p = 0.003) and a decrease in consuming the largest portions during the afternoon and evening (p = 0.030). Plasma levels of fasting glucose, leptin and ghrelin significantly decreased (p = 0.006; p = 0.0.043); in contrast, the level of adiponectin significantly increased (p < 0.001). Conclusions Sleeve gastrectomy and follow-up nutritional therapy resulted in a significant body weight reduction within 1 year after surgery. An improvement of certain dietary habits in patients was registered. At 12 months after surgery, there were no statistically significant differences in decreases in ghrelin and leptin concentrations between patients without changed appetite and those reporting decreased appetite. PMID:25561993

  1. Prolactin is a major inhibitor of hepatic Leptin A synthesis and secretion: studies utilizing a homologous Leptin A ELISA in the tilapia.

    PubMed

    Douros, Jonathan D; Baltzegar, David A; Breves, Jason P; Lerner, Darren T; Seale, Andre P; Gordon Grau, E; Borski, Russell J

    2014-10-01

    The present study identifies regulatory interactions between leptin A (LepA) and the pituitary hormone prolactin (PRL). In order to measure tilapia (Oreochromis mossambicus) LepA, an enzyme-linked immunosorbent assay (ELISA) utilizing a rabbit polyclonal antibody specific to tilapia LepA was first developed. The antibody shows strong cross reactivity to recombinant tilapia LepA (rtLepA), and a corresponding 16kDa protein in both tilapia and striped bass plasma, but not to recombinant human leptin (rhLep). The assay has a linear detection range of 0.25-1000nM, with intra- and interassay variability of 9% and 16%, respectively. Plasma LepA levels measured in tilapia ranged from 0.8 to 3.9nM, similar to that found for other vertebrates. Hypophysectomy (Hx) increased circulating LepA and lepa mRNA levels in the liver, the dominant source of hormone production. Adminstration of ovine PRL (oPRL, 5μg/g BW) to Hx fish restored circulating LepA and hepatic lepa mRNA levels to those of control fish. Additionally, oPRL reduced lepa mRNA levels in a dose-dependent fashion in cultured hepatocytes following an 18h incubation. Previous work in our lab indicates that rhLep stimulates PRL release in vitro from tilapia pituitaries. Here, both rtLepA and rhLep (0.5μg/g BW) increased mRNA expression of tilapia prolactin mRNAs (prl1, prl2) in the pituitary in vivo. These results demonstrate that LepA enhances pituitary prolactin synthesis and release, while PRL in turn inhibits hepatic leptin secretion and synthesis in teleosts. We postulate this regulatory interaction may be necessary for mobilizing energy reserves during acute hyperosmotic adaptation. PMID:24662392

  2. Leptin expression affects metabolic rate in zebrafish embryos (D. rerio).

    PubMed

    Dalman, Mark R; Liu, Qin; King, Mason D; Bagatto, Brian; Londraville, Richard L

    2013-01-01

    We used antisense morpholino oligonucleotide technology to knockdown leptin-(A) gene expression in developing zebrafish embryos and measured its effects on metabolic rate and cardiovascular function. Using two indicators of metabolic rate, oxygen consumption was significantly lower in leptin morphants early in development [<48 hours post-fertilization (hpf)], while acid production was significantly lower in morphants later in development (>48 hpf). Oxygen utilization rates in <48 hpf embryos and acid production in 72 hpf embryos could be rescued to that of wildtype embryos by recombinant leptin coinjected with antisense morpholino. Leptin is established to influence metabolic rate in mammals, and these data suggest leptin signaling also influences metabolic rate in fishes.

  3. Comparative endocrinology of leptin: Assessing function in a phylogenetic context

    PubMed Central

    Londraville, Richard L.; Macotela, Yazmin; Duff, Robert J.; Easterling, Marietta R.; Liu, Qin; Crespi, Erica J.

    2014-01-01

    As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans. PMID:24525452

  4. Oestradiol modulates the effects of leptin on energy homeostasis by corticotrophin-releasing factor type 2 receptor.

    PubMed

    Marangon, P B; Silva, L E C M; Rorato, R; Gomiero Alves, P; Antunes-Rodrigues, J; Elias, L L K

    2014-11-01

    In addition to its action in the control of the hypothalamic-pituitary-adrenal axis, corticotrophin-releasing factor (CRF) has been described as an anorexigenic neuropeptide, modulating food intake and energy expenditure. CRF synthesis is influenced by leptin, which would act to increase CRF neurone activation in the paraventricular nucleus (PVN). Gonadal hormones also participate in the regulation of energy homeostasis. The reduction of food intake and body weight gain in ovariectomised (OVX) rats treated with oestradiol is associated with an increase in CRF mRNA expression in the PVN. The present study aimed to investigate the role of CRF as a mediator of leptin responsiveness in the presence of oestradiol. Wistar female rats were bilaterally OVX and divided into three groups: OVX, OVX+E (i.e. treated with oestradiol) and OVX+PF (i.e. OVX pairfed with OVX+E). The rats received daily s.c. injections of either oestradiol cypionate or vehicle for 8 days. To evaluate the role of CRF on the effects of leptin, we performed an i.c.v. leptin injection (10 μg/5 μl) with or without previous i.c.v. treatment with an CRF-R2 antagonist. We observed that oestradiol replacement in OVX rats reduced body weight gain and food intake. The effects of exogenous leptin administration with respect to decreasing food intake and body weight, and increasing uncoupling protein-1 expression in the brown adipose tissue and neuronal activation in the arcuate nucleus, were reversed by previous administration of a CRF-R2 antagonist only in oestradiol-treated OVX rats. These effects appear to be mediated by CRF-2 receptor because the antagonist of this receptor reversed the action of oestradiol on the effects of leptin.

  5. Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes.

    PubMed

    Scarpace, P J; Matheny, M; Kirichenko, N; Gao, Y X; Tümer, N; Zhang, Y

    2013-02-01

    High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes.

  6. Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity.

    PubMed

    Roumaud, Pauline; Martin, Luc J

    2015-10-01

    The increase in obesity rate is a major public health issue associated with increased pathological conditions such as type 2 diabetes or cardiovascular diseases. Obesity also contributes to decreased testosterone levels in men. Indeed, the adipose tissue is an endocrine organ which produces hormones such as leptin, adiponectin and resistin. Obesity results in pathological accumulations of leptin and resistin, whereas adiponectin plasma levels are markedly reduced, all having a negative impact on testosterone synthesis. This review focuses on current knowledge related to transcriptional regulation of Leydig cells' steroidogenesis by leptin, adiponectin and resistin. We show that there are crosstalks between the regulatory mechanisms of these hormones and androgen production which may result in a dramatic negative influence on testosterone plasma levels. Indeed leptin, adiponectin and resistin can impact expression of different steroidogenic genes such as Star, Cyp11a1 or Sf1. Further investigations will be required to better define the implications of adipose derived hormones on regulation of steroidogenic genes expression within Leydig cells under physiological as well as pathological conditions.

  7. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice.

    PubMed

    Pan, Weihong; Hsuchou, Hung; He, Yi; Sakharkar, Amul; Cain, Courtney; Yu, Chuanhui; Kastin, Abba J

    2008-06-01

    The agouti viable yellow (A vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, (125)I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young A vy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A vy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) A vy and B6 mice. Higher ObRb mRNA was seen in the A vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the A vy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

  8. Reduced Melanocortin Production Causes Sexual Dysfunction in Male Mice With POMC Neuronal Insulin and Leptin Insensitivity

    PubMed Central

    Faulkner, Latrice D.; Dowling, Abigail R.; Stuart, Ronald C.; Nillni, Eduardo A.

    2015-01-01

    Proopiomelanocortin (POMC)-derived peptides like α-melanocyte-stimulating hormone (MSH) substantially improve hepatic insulin sensitivity and regulate energy expenditure. Melanocortinergic agents are also powerful inducers of sexual arousal that are being investigated for a possible therapeutic role in erectile dysfunction. It is currently unclear whether reduced melanocortin (MC) activity may contribute to the sexual dysfunction accompanying obesity and type 2 diabetes. Male rodents with leptin and insulin resistance targeted to POMC neurons (leptin receptor [LepR]/insulin receptor [IR]POMC mice) exhibit obesity, hyperinsulinemia, hyperglycemia, and systemic insulin resistance. In this study, we demonstrate that LepR/IRPOMC males are also subfertile due to dramatic alterations in sexual behavior. Remarkably, these reproductive changes are accompanied by decreased α-MSH production not present when a single receptor type is deleted. Unexpectedly, behavioral sensitivity to α-MSH and MC receptor expression are also reduced in LepR/IRPOMC males, a potential adaptation of the MC system to altered α-MSH production. Together, these results suggest that concurrent insulin and leptin resistance in POMC neurons in individuals with obesity or type 2 diabetes can reduce endogenous α-MSH levels and impair sexual function. PMID:25590244

  9. Pineal melatonin is a circadian time-giver for leptin rhythm in Syrian hamsters

    PubMed Central

    Chakir, Ibtissam; Dumont, Stéphanie; Pévet, Paul; Ouarour, Ali; Challet, Etienne; Vuillez, Patrick

    2015-01-01

    Nocturnal secretion of melatonin from the pineal gland may affect central and peripheral timing, in addition to its well-known involvement in the control of seasonal physiology. The Syrian hamster is a photoperiodic species, which displays gonadal atrophy and increased adiposity when adapted to short (winter-like) photoperiods. Here we investigated whether pineal melatonin secreted at night can impact daily rhythmicity of metabolic hormones and glucose in that seasonal species. For that purpose, daily variations of plasma leptin, cortisol, insulin and glucose were analyzed in pinealectomized hamsters, as compared to sham-operated controls kept under very long (16 h light/08 h dark) or short photoperiods (08 h light/16 h dark). Daily rhythms of leptin under both long and short photoperiods were blunted by pinealectomy. Furthermore, the phase of cortisol rhythm under a short photoperiod was advanced by 5.6 h after pinealectomy. Neither plasma insulin, nor blood glucose displays robust daily rhythmicity, even in sham-operated hamsters. Pinealectomy, however, totally reversed the decreased levels of insulin under short days and the photoperiodic variations in mean levels of blood glucose (i.e., reduction and increase in long and short days, respectively). Together, these findings in Syrian hamsters show that circulating melatonin at night drives the daily rhythmicity of plasma leptin, participates in the phase control of cortisol rhythm and modulates glucose homeostasis according to photoperiod-dependent metabolic state. PMID:26074760

  10. The Role of PVH Circuits in Leptin Action and Energy Balance

    PubMed Central

    Sutton, Amy K.; Myers, Martin G.; Olson, David P.

    2016-01-01

    Summary While it has been clear that the brain regulates feeding behaviour and energy expenditure, the major determinants of energy balance and adiposity, roles for individual brain regions (and specific cell types within these regions) in the control of energy balance were not understood until very recently; these details continue to emerge rapidly. Much of what we now know flows from the discoveries of leptin and the hypothalamic melanocortin system, which define circuits crucial for the control of energy balance. Within the brain, hypothalamic circuits play a crucial role in the control of feeding and energy expenditure. Within the hypothalamus, the arcuate nucleus (ARC) functions as an entry point gateway for hormonal signals of energy balance, such as leptin; the ARC also contains the soma of melanocortinergic neurons. The paraventricular hypothalamic nucleus (PVH) receives direct melanocortin input, along with other integrated signals regarding energy balance, and mediates the majority of hypothalamic output to control feeding and energy expenditure. Herein, we review the structure and function of the ARC-PVH circuit in leptin action, in addition to it’s role in the control of feeding behavior and energy expenditure. PMID:26863324

  11. The Role of PVH Circuits in Leptin Action and Energy Balance.

    PubMed

    Sutton, Amy K; Myers, Martin G; Olson, David P

    2016-01-01

    Although it has been known for more than a century that the brain controls overall energy balance and adiposity by regulating feeding behavior and energy expenditure, the roles for individual brain regions and neuronal subtypes were not fully understood until recently. This area of research is active, and as such our understanding of the central regulation of energy balance is continually being refined as new details emerge. Much of what we now know stems from the discoveries of leptin and the hypothalamic melanocortin system. Hypothalamic circuits play a crucial role in the control of feeding and energy expenditure, and within the hypothalamus, the arcuate nucleus (ARC) functions as a gateway for hormonal signals of energy balance, such as leptin. It is also well established that the ARC is a primary residence for hypothalamic melanocortinergic neurons. The paraventricular hypothalamic nucleus (PVH) receives direct melanocortin input, along with other integrated signals that affect energy balance, and mediates the majority of hypothalamic output to control both feeding and energy expenditure. Herein, we review in detail the structure and function of the ARC-PVH circuit in mediating leptin signaling and in regulating energy balance. PMID:26863324

  12. Relationships between plasma leptin levels, leptin G2548A, leptin receptor Gln223Arg polymorphisms and gestational diabetes mellitus in Chinese population