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Christian Bjorbaek - One of the best experts on this subject based on the ideXlab platform.

  • divergent Leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats
    Endocrinology, 2008
    Co-Authors: Kevin Gamber, Harvey J Grill, Christian Bjorbaek
    Abstract:

    The central targets mediating the anorectic and other actions of Leptin have yet to be fully identified. Although previous studies focused on the hypothalamus, Leptin also acts on neurons in extrahypothalamic sites, including the nucleus of the solitary tract (NTS). Moreover, injection of Leptin into the NTS of rats suppresses food intake. Within the central nervous system, glucagon-like peptide (GLP-1), a product of proglucagon, is synthesized almost exclusively in neurons of the NTS. Intracerebroventricular administration of GLP-1 inhibits energy intake, and GLP-1 receptor antagonists attenuate the anorexic effects of Leptin in rats. To examine whether NTS proglucagon neurons are directly regulated by Leptin, we performed double GLP-1 and phosphorylation of signal transducer and activator of transcription-3 immunohistochemistry on brain sections from ip Leptin-treated mice and rats. Leptin induced phosphorylation of signal transducer and activator of transcription-3 in 100% of GLP-1 cells in the caudal brainstem of mice. In striking contrast, 0% of GLP-1-positive neurons in rats responded to Leptin. We then measured regulation of NTS proglucagon mRNA using real-time RT-PCR in mice and rats fed ad libitum, fasted, or fasted and treated ip with Leptin. In mice, proglucagon mRNA fell by fasting, and this was prevented by Leptin administration. In rats, by contrast, proglucagon mRNA was unaffected by either fasting or Leptin. Taken together, our studies reveal direct regulation of proglucagon neurons by Leptin in mice but not rats along with corresponding species differences in the regulation of proglucagon mRNA expression. These data, combined with previous results, suggest a different mechanism of interaction between Leptin and NTS proglucagon neurons in mice and rats.

  • region specific Leptin resistance within the hypothalamus of diet induced obese mice
    Endocrinology, 2004
    Co-Authors: Heike Munzberg, Jeffrey S. Flier, Christian Bjorbaek
    Abstract:

    Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum Leptin and a decreased response to exogenous Leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of Leptin resistance within individual brain regions has not been reported. We first mapped Leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, Leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained Leptin sensitive. Reduced Leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for Leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the Leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of Leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively Leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in Leptin action in the ARC may play a role in the pathogenesis of Leptin-resistant obesity.

  • enhanced Leptin sensitivity and attenuation of diet induced obesity in mice with haploinsufficiency of socs3
    Nature Medicine, 2004
    Co-Authors: Jane K Howard, Christian Bjorbaek, Belinda J Cave, Laura J Oksanen, Iphigenia Tzameli, Jeffrey S. Flier
    Abstract:

    Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways1,2. Resistance to the weight reducing effects of Leptin is a feature of most cases of human and rodent obesity1,2, yet the molecular basis of Leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a Leptin-induced negative regulator of Leptin receptor signaling and potential mediator of Leptin resistance3,4,5. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in Leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3+/−). We report here that Socs3+/− mice display greater Leptin sensitivity than wild-type control mice: Socs3+/− mice show both enhanced weight loss and increased hypothalamic Leptin receptor signaling in response to exogenous Leptin administration. Furthermore, Socs3+/− mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of Leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.

  • two defects contribute to hypothalamic Leptin resistance in mice with diet induced obesity
    Journal of Clinical Investigation, 2000
    Co-Authors: Karim Elhaschimi, Christian Bjorbaek, Dominique D Pierroz, Stanley M Hileman, Jeffrey S. Flier
    Abstract:

    Obesity in humans and in rodents is usually associated with high circulating Leptin levels and Leptin resistance. To examine the molecular basis for Leptin resistance, we determined the ability of Leptin to induce hypothalamic STAT3 (signal transducer and activator of transcription) signaling in C57BL/6J mice fed either low-fat or high-fat diets. In mice fed the low-fat diet, Leptin activated STAT3 signaling when administered via the intraperitoneal (ip) or the intracerebroventricular (icv) route, with the half-maximal dose being 30-fold less when given by the icv route. The high-fat diet increased body-weight gain and plasma Leptin levels. After 4 weeks on the diet, hypothalamic STAT3 signaling after ip Leptin administration was equivalent in both diet groups. In contrast, peripherally administered Leptin was completely unable to activate hypothalamic STAT3 signaling, as measured by gel shift assay after 15 weeks of high-fat diet. Despite the absence of detectable signaling after peripheral Leptin at 15 weeks, the mice fed the high-fat diet retained the capacity to respond to icv Leptin, although the magnitude of STAT3 activation was substantially reduced. These results suggest that Leptin resistance induced by a high-fat diet evolves during the course of the diet and has at least two independent causes: an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral Leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in Leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.

Andre Bado - One of the best experts on this subject based on the ideXlab platform.

  • duodenal Leptin stimulates cholecystokinin secretion evidence of a positive Leptin cholecystokinin feedback loop
    Diabetes, 2003
    Co-Authors: Sandra Guilmeau, Marion Buyse, Annick Tsocas, Jean Pierre Laigneau, Andre Bado
    Abstract:

    Some of the actions of Leptin depend on cholecystokinin (CCK). However, it is unknown whether Leptin modulates the release of CCK. Here, we demonstrate in vitro that Leptin induces the phosphorylation of extracellular signal–related kinase (ERK)-1/2 proteins and increases CCK release (EC50 = 0.23 nmol/l) in CCK-secreting STC-1 cells. We showed that rat duodenal juice contains Leptin that circulates free and bound to macromolecules, suggesting that Leptin has a lumenal action on the intestine. In vivo in the rat, duodenal infusion of Leptin increased plasma CCK at levels comparable to those induced by feeding. Moreover, meal-induced increases in plasma CCK were markedly reduced in obese fa / fa rats, whereas the mobilization of the gastric Leptin pool was similar in lean and obese Zucker rats. The release of CCK by Leptin presumably generates a positive feedback loop. Indeed, the blockade of CCK receptors reversed the meal reduction of the stomach Leptin pool and the meal-increased plasma insulin, consistent with the previous concept of an entero-insular axis. Collectively, these data support a novel mode of action of Leptin where Leptin and CCK may potentiate their own effects by cross-stimulating their secretion. The impairment of this Leptin-CCK loop may have pathological implications related to obesity and diabetes.

  • vagal stimulation rapidly increases Leptin secretion in human stomach
    Gastroenterology, 2002
    Co-Authors: Iradj Sobhani, Marion Buyse, Dominique Henin, Jean Pierre Laigneau, Healene Goiot, Nina Weber, Jean Claude Soule, Andre Bado
    Abstract:

    Abstract Background & Aims: Leptin production has been reported in the rat and in human stomach. It initiates intestinal nutrient absorption. In this study, we analyzed the effect of vagal stimulation on Leptin release in the human stomach. Methods: We studied the secretion of gastric acid and Leptin on stimulation with insulin (a stimulant of vagal pathways via hypoglycemia) and pentagastrin in 11 healthy men (normal endoscopy and normal histological gastric mucosa), 5 with previous highly selective vagotomy (HSV), and 6 without HSV. Fundic biopsies were performed for immunostaining of Leptin. Results: There was no difference between the 2 groups with respect to age, body mass index, basal Leptin (4.8 ± 1.2 ng/15 minutes) and gastric acid (0.7 ± 0.2 mmol/15 minutes) outputs. Leptin-immunoreactivity was found in the fundic glands, and its distribution and density were similar in 2 groups. Insulin caused a rapid (15-minute) increase in Leptin output in men without HSV (31 ± 9 ng/15 minutes), but not in those with HSV (7.7 ± 3.2 ng/15 minutes). Insulin-stimulated gastric Leptin was biphasic, with a rapid increase (15 minutes after injection) followed by a second steady and sustained increase (39.9 ± 7.6 ng/15 minutes at 120 minutes after injection). Pentagastrin increased gastric Leptin output in individuals with (30 ± 4.9 ng/15 minutes) and without (26 ± 3.2 ng/15 minutes) HSV. Insulin and pentagastrin did not modify plasma Leptin, whatever HSV status. Conclusions: Vagal stimulation of Leptin release in the human stomach suggests that Leptin is released during the cephalic phase of gastric secretion. Luminal Leptin may be involved in vagus-mediated intestinal functions. GASTROENTEROLOGY 2002;122:259-263

  • expression and regulation of Leptin receptor proteins in afferent and efferent neurons of the vagus nerve
    European Journal of Neuroscience, 2001
    Co-Authors: Marion Buyse, Bjorn Meister, L Moizo, Sandra Guilmeau, Marielouise Ovesjo, Helene Goiot, Gabriel Peranzi, Francine Walker, Miguel J M Lewin, Andre Bado
    Abstract:

    : Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic Leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between Leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of Leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) Leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of Leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of Leptin receptors and the Leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of Leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, Leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal Leptin receptors, apart from being activated by adipocyte-derived Leptin, may also be influenced by Leptin produced by the stomach. This may explain the synergistic action of Leptin and CCK on neuronal activity in the NTS and on food intake.

  • Leptin secretion and Leptin receptor in the human stomach
    Gut, 2000
    Co-Authors: Iradj Sobhani, Andre Bado, C Vissuzaine, Marion Buyse, Stephanie Kermorgant, J P Laigneau, Samir Attoub, T Lehy, Dominique Henin, M Mignon
    Abstract:

    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.

Michael W Schwartz - One of the best experts on this subject based on the ideXlab platform.

  • obesity and Leptin resistance distinguishing cause from effect
    Trends in Endocrinology and Metabolism, 2010
    Co-Authors: Marti G Myers, Randy J Seeley, Rudolph L Leibel, Michael W Schwartz
    Abstract:

    Because Leptin reduces food intake and body weight, the coexistence of elevated Leptin levels with obesity is widely interpreted as evidence of 'Leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate Leptin signaling (referred to here as 'cellular Leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'Leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular Leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.

  • immunocytochemistry and laser capture microdissection for real time quantitative pcr identify hindbrain neurons activated by interaction between Leptin and cholecystokinin
    Journal of Histochemistry and Cytochemistry, 2008
    Co-Authors: D J L Williams, Michael W Schwartz, Scot L Bastian, James E Blevins, Denis G Baskin
    Abstract:

    Current evidence suggests that Leptin reduces food intake in part by enhancing the hindbrain neuronal response to meal-related gastrointestinal signals, including cholecystokinin (CCK), but the phenotypes of the relevant cells are not known. To identify neurons that participate in this interaction in the rat nucleus of the solitary tract (NTS), we induced c-Fos gene expression in NTS neurons with Leptin and CCK. We focused on NTS catecholamine neurons because these cells have been implicated in the feeding response to CCK. Hindbrain sections from rats that received CCK with or without Leptin pretreatment were immunostained for c-Fos and tyrosine hydroxylase (TH) by a double immunofluorescence procedure. Leptin pretreatment increased the number of NTS cells expressing c-Fos-like immunoreactivity (cFLI) 3-fold relative to CCK alone, but the number of TH-positive cells with cFLI was increased 6-fold. Next, cells detected by immunofluorescence for TH were collected by laser capture microdissection and pooled for real-time quantitative PCR of c-Fos mRNA. Here, neither le0ptin nor CCK alone affected the relative amount of mRNA in the TH cell–enriched samples, but Leptin plus CCK substantially increased c-Fos mRNA content. These histochemical findings identify hindbrain catecholamine cells as potential mediators of the interaction between Leptin and CCK. (J Histochem Cytochem 56:285–293, 2008)

  • Leptin increases hypothalamic pro opiomelanocortin mrna expression in the rostral arcuate nucleus
    Diabetes, 1997
    Co-Authors: Michael W Schwartz, Stephe C Woods, Randy J Seeley, David S Weigle, Arthur L Campfield, Paul Burn, Denis G Baskin
    Abstract:

    Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC) precursor, that act in the brain to reduce food intake and are potential mediators of Leptin action. In the forebrain, melanocortins are derived from POMC-containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis that these POMC neurons are regulated by Leptin, we used in situ hybridization to determine whether reduced Leptin signaling (as occurs in fasting), genetic Leptin deficiency (in obese ob/ob mice), or genetic Leptin resistance (in obese db/db mice) lower expression of POMC mRNA. We further hypothesized that Leptin administration would raise hypothalamic POMC mRNA levels in Leptin-deficient animals, but not in mice with defective Leptin receptors. In wild-type mice ( n = 12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by 53%, relative to values in fed controls ( n = 8; P ob/ob ( n = 6) and db/db mice ( n = 6), respectively, as compared with wild-type mice ( n = 5) ( P ob/ob mice ( n = 8) by 73% over saline-treated ob/ob control values ( n = 8; P db/db mice ( n = 6). In normal rats, two injections of a low dose of Leptin (3.5 μg) into the third cerebral ventricle ( n = 15) during a 40-h period of fasting also increased POMC mRNA levels in the rostral arcuate nucleus to values 39% greater than those in vehicle-treated controls ( n = 14; P = 0.02). We conclude that reduced central nervous system Leptin signaling owing to fasting or to genetic defects in Leptin or its receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that Leptin reverses this effect in ob/ob , but not db/db , mice suggests that Leptin stimulates arcuate nucleus POMC gene expression via a pathway involving Leptin receptors. These findings support the hypothesis that Leptin signaling in the brain involves activation of the hypothalamic melanocortin system.

  • identification of targets of Leptin action in rat hypothalamus
    Journal of Clinical Investigation, 1996
    Co-Authors: Michael W Schwartz, Randy J Seeley, Paul Burn, L A Campfield, Denis G Baskin
    Abstract:

    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.

  • Cerebrospinal fluid Leptin levels: Relationship to plasma levels and to adiposity in humans
    Nature Medicine, 1996
    Co-Authors: Michael W Schwartz, Elaine R. Peskind, Murray A. Raskind, Edward J. Boyko, Daniel Porte
    Abstract:

    The adipocyte hormone, Leptin (OB protein), is proposed to be an “adiposity signal” that acts in the brain to lower food intake and adiposity1–5. As plasma Leptin levels are elevated in most overweight individuals, obesity may be associated with Leptin resistance6,7. To investigate the mechanisms underlying brain Leptin uptake and to determine whether reduced uptake may contribute to Leptin resistance, we measured immunoreactive Leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; P = 0.0001). Like levels in plasma, CSF Leptin levels were correlated to body mass index (r = 0.43; P = 0.001), demonstrating that plasma Leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma Leptin ratio) was lower among those in the highest as compared with the lowest plasma Leptin quintile (5.4–fold difference). We hypothesize that a saturable mechanism mediates CSF Leptin transport, and that reduced efficiency of brain Leptin delivery among obese individuals with high plasma Leptin levels results in apparent Leptin resistance.

Christos S Mantzoros - One of the best experts on this subject based on the ideXlab platform.

  • Leptin in human physiology and pathophysiology
    American Journal of Physiology-endocrinology and Metabolism, 2011
    Co-Authors: Christos S Mantzoros, Faido Magkos, Mary Inkoette, Elizabeth Sienkiewicz, Tina Dardeno, Sangyong Kim, Olepette R Hamnvik, Anastasia Koniaris
    Abstract:

    Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for Leptin to regulate a number of physiological functions. Available evidence from human studies indicates that Leptin has a mainly permissive role, with Leptin administration being effective in states of Leptin deficiency, less effective in states of Leptin adequacy, and largely ineffective in states of Leptin excess. Results from interventional studies in humans demonstrate that Leptin administration in subjects with congenital complete Leptin deficiency or subjects with partial Leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, Leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, Leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, Leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, Leptin's effects are largely absent in the obese hyperLeptinemic state, probably due to Leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of Leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of Leptin and the potential clinical applications of Leptin or its analogs in human therapeutics.

  • Leptin in immunology
    Journal of Immunology, 2005
    Co-Authors: Giuseppe Matarese, Stergios J Moschos, Christos S Mantzoros
    Abstract:

    Leptin is an adipokine which conveys information on energy availability. In humans, Leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, Leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, Leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of Leptin in the pathophysiology of immune responses.

  • recombinant methionyl human Leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor α receptor levels in humans with relati
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Jean L Chan, Barbara B Kahn, Stergios J Moschos, John Bullen, Kathleen Heist, Xian Li, Christos S Mantzoros
    Abstract:

    Studies of congenital complete Leptin deficiency in animals and humans support a role for Leptin in regulating immune function. Whether acquired relative Leptin deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative Leptin deficiency and recombinant methionyl human Leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative Leptin deficiency and/or increasing circulating Leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term Leptin deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time h...

  • human Leptin levels are pulsatile and inversely related to pituitary adrenal function
    Nature Medicine, 1997
    Co-Authors: Julio Licinio, George P Chrousos, Christos S Mantzoros, Andre B Negrao, Giovanni Cizza, Ma L I Wong, Peter B Bongiorno, Brian Karp, Christine Allen, Jeffrey S. Flier
    Abstract:

    Leptin communicates nutritional status to regulatory centers in the brain1,2. Because peripheral Leptin influences the activity of the highly pulsatile adrenal and gonadal axes3,4, we sought to determine whether Leptin levels in the blood are pulsatile. We measured circulating Leptin levels every 7 minutes for 24 hours, in six healthy men, and found that total circulating Leptin levels exhibited a pattern indicative of pulsatile release, with 32.0 ± 1.5 pulses every 24 hours and a pulse duration of 32.8 ± 1.6 minutes. We also show an inverse relation between rapid fluctuations in plasma levels of Leptin and those of adrenocorticotropic hormone (ACTH) and cortisol that could not be accounted for on the basis of glucocorticoid suppression of Leptin. As Leptin levels are pulsatile, we propose that a key function of the CNS is regulated by a peripheral pulsatile signal. In a separate pilot study we compared Leptin pulsatility in 414 plasma samples collected every 7 minutes for 24 hours from one obese woman and one normal-weight woman. We found that high Leptin levels in the obese subject were due solely to increased Leptin pulse height; all concentration-independent pulsatility parameters were almost identical in the two women. Leptin pulsatility therefore can be preserved in the obese.

  • role of Leptin in the neuroendocrine response to fasting
    Nature, 1996
    Co-Authors: Rexford S Ahima, Christos S Mantzoros, Daniel Prabakara, Adford Lowell, Eleftheria Maratosflie, Jeffrey S Flie
    Abstract:

    A TOTAL deficiency in or resistance to the protein Leptin causes severe obesity1–4. As Leptin levels rise with increasing adiposity in rodents5 and man6,7, it is proposed to act as a negative feedback 'adipostatic signal' to brain centres controlling energy homeostasis, limiting obesity in times of nutritional abundance1,3. Starvation is also a threat to homeostasis that triggers adaptive responses8–12, but whether Leptin plays a role in the physiology of starvation is unknown. Leptin concentration falls during starvation13 and totally Leptin-deficient ob/ob mice have neuroendocrine abnormalities similar to those of starvation14, suggesting that this may be the case. Here we show that preventing the starvation-induced fall in Leptin with exogenous Leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starvation-induced delay in ovulation in female mice. In contrast, Leptin repletion during this period of starvation has little or no effect on body weight, blood glucose or ketones. We propose that regulation of the neuroendocrine system during starvation could be the main physiological role of Leptin.

Denis G Baskin - One of the best experts on this subject based on the ideXlab platform.

  • immunocytochemistry and laser capture microdissection for real time quantitative pcr identify hindbrain neurons activated by interaction between Leptin and cholecystokinin
    Journal of Histochemistry and Cytochemistry, 2008
    Co-Authors: D J L Williams, Michael W Schwartz, Scot L Bastian, James E Blevins, Denis G Baskin
    Abstract:

    Current evidence suggests that Leptin reduces food intake in part by enhancing the hindbrain neuronal response to meal-related gastrointestinal signals, including cholecystokinin (CCK), but the phenotypes of the relevant cells are not known. To identify neurons that participate in this interaction in the rat nucleus of the solitary tract (NTS), we induced c-Fos gene expression in NTS neurons with Leptin and CCK. We focused on NTS catecholamine neurons because these cells have been implicated in the feeding response to CCK. Hindbrain sections from rats that received CCK with or without Leptin pretreatment were immunostained for c-Fos and tyrosine hydroxylase (TH) by a double immunofluorescence procedure. Leptin pretreatment increased the number of NTS cells expressing c-Fos-like immunoreactivity (cFLI) 3-fold relative to CCK alone, but the number of TH-positive cells with cFLI was increased 6-fold. Next, cells detected by immunofluorescence for TH were collected by laser capture microdissection and pooled for real-time quantitative PCR of c-Fos mRNA. Here, neither le0ptin nor CCK alone affected the relative amount of mRNA in the TH cell–enriched samples, but Leptin plus CCK substantially increased c-Fos mRNA content. These histochemical findings identify hindbrain catecholamine cells as potential mediators of the interaction between Leptin and CCK. (J Histochem Cytochem 56:285–293, 2008)

  • Leptin increases hypothalamic pro opiomelanocortin mrna expression in the rostral arcuate nucleus
    Diabetes, 1997
    Co-Authors: Michael W Schwartz, Stephe C Woods, Randy J Seeley, David S Weigle, Arthur L Campfield, Paul Burn, Denis G Baskin
    Abstract:

    Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC) precursor, that act in the brain to reduce food intake and are potential mediators of Leptin action. In the forebrain, melanocortins are derived from POMC-containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis that these POMC neurons are regulated by Leptin, we used in situ hybridization to determine whether reduced Leptin signaling (as occurs in fasting), genetic Leptin deficiency (in obese ob/ob mice), or genetic Leptin resistance (in obese db/db mice) lower expression of POMC mRNA. We further hypothesized that Leptin administration would raise hypothalamic POMC mRNA levels in Leptin-deficient animals, but not in mice with defective Leptin receptors. In wild-type mice ( n = 12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by 53%, relative to values in fed controls ( n = 8; P ob/ob ( n = 6) and db/db mice ( n = 6), respectively, as compared with wild-type mice ( n = 5) ( P ob/ob mice ( n = 8) by 73% over saline-treated ob/ob control values ( n = 8; P db/db mice ( n = 6). In normal rats, two injections of a low dose of Leptin (3.5 μg) into the third cerebral ventricle ( n = 15) during a 40-h period of fasting also increased POMC mRNA levels in the rostral arcuate nucleus to values 39% greater than those in vehicle-treated controls ( n = 14; P = 0.02). We conclude that reduced central nervous system Leptin signaling owing to fasting or to genetic defects in Leptin or its receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that Leptin reverses this effect in ob/ob , but not db/db , mice suggests that Leptin stimulates arcuate nucleus POMC gene expression via a pathway involving Leptin receptors. These findings support the hypothesis that Leptin signaling in the brain involves activation of the hypothalamic melanocortin system.

  • identification of targets of Leptin action in rat hypothalamus
    Journal of Clinical Investigation, 1996
    Co-Authors: Michael W Schwartz, Randy J Seeley, Paul Burn, L A Campfield, Denis G Baskin
    Abstract:

    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.

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