scholarly journals Inactivation of Signal Transducer and Activator of Transcription 3 in Proopiomelanocortin (Pomc) Neurons Causes Decreased Pomc Expression, Mild Obesity, and Defects in Compensatory Refeeding

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 72-80 ◽  
Author(s):  
Allison W. Xu ◽  
Linda Ste-Marie ◽  
Christopher B. Kaelin ◽  
Gregory S. Barsh
Keyword(s):  
Intracellular Signaling ◽  
Leptin Receptor ◽  
Neuronal Response ◽  
Fold Increase ◽  
Total Body Weight ◽  
Mutant Mice ◽  
Signal Transducer ◽  
Energy Status ◽  
Total Body ◽  
Transcription 3

Leptin is an adipocyte-derived hormone that signals body energy status to the brain by acting on multiple neuronal subgroups in the hypothalamus, including those that express proopiomelanocortin (Pomc) and agouti-related protein (Agrp). Signal transducer and activator of transcription 3 (Stat3) is an important intracellular signaling molecule activated by leptin, and previous studies have shown that mice carrying a mutated leptin receptor that abolished Stat3 binding are grossly obese. To determine the extent to which Stat3 signaling in Pomc neurons was responsible for these effects, we constructed Pomc-specific Stat3 mutants using a Cre recombinase transgene driven by the Pomc promoter. We find that Pomc expression is diminished in the mutant mice, suggesting that Stat3 is required for Pomc transcription. Pomc-specific Stat3 female mutant mice exhibit a 2-fold increase in fat pad mass but only a slight increase in total body weight. Mutant mice remain responsive to leptin-induced hypophagia and are not hypersensitive to a high-fat diet; however, mutant mice fail to mount a normal compensatory refeeding response. These results demonstrate a requirement for Stat3 in transcriptional regulation of Pomc but indicate that this circuit is only one of several components that underlie the neuronal response to leptin and the role of Stat3 in that response.

scholarly journals Increased Hypothalamic Signal Transducer and Activator of Transcription 3 Phosphorylation after Hindbrain Leptin Injection

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1509-1519 ◽  
Author(s):  
Marieke Ruiter ◽  
Patricia Duffy ◽  
Steven Simasko ◽  
Robert C. Ritter
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Leptin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Solitary Tract ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
Transcription 3

Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated. Confirming earlier work, we found that leptin produced comparable reductions of feeding and body weight when injected into the lateral ventricle or the fourth ventricle. We also found that lateral and fourth ventricle leptin injections produced comparable increases of STAT3 phosphorylation in both the hindbrain and the hypothalamus. Moreover, injection of 50 ng of leptin directly into the nucleus of the solitary tract also increased STAT3 phosphorylation in the hypothalamic arcuate and ventromedial nuclei. Increased hypothalamic STAT3 phosphorylation was not due to elevation of blood leptin concentrations and the pattern of STAT3 phosphorylation did not overlap distribution of the retrograde tracer, fluorogold, injected via the same cannula. Our observations indicate that even small leptin doses administered to the hindbrain can trigger leptin-related signaling in the forebrain, and raise the possibility that STAT3 phosphorylation in the hypothalamus may contribute to behavioral and metabolic changes observed after hindbrain leptin injections.

scholarly journals Expression of the Leptin Receptor during Germ Cell Development in the Mouse Testis*

Endocrinology ◽  
2000 ◽  
Vol 141 (7) ◽  
pp. 2624-2630 ◽  
Author(s):  
Talal El-Hefnawy ◽  
Sergey Ioffe ◽  
Martin Dym
Keyword(s):  
Germ Cells ◽  
Messenger Rna ◽  
Leptin Receptor ◽  
Age Groups ◽  
Mouse Testis ◽  
Seminiferous Tubules ◽  
Signal Transducer ◽  
Direct Role ◽  
Specific Localization ◽  
Transcription 3

Leptin, a recently identified hormonal product of the ob gene, is known to regulate appetite, body metabolism, and reproductive functions. We investigated the expression of the leptin receptor (Ob-R) in testes from different age groups. The messenger RNA for Ob-R was found in testes from all age groups using RT-PCR. Using immunohistochemistry, we observed age- and stage-dependent distribution of the Ob-R in mouse testis. In testis of 5-day-old mice, its expression was mainly in type A spermatogonia. In the 20- and 30-day-old testis, Ob-R expression was in the spermatocytes; in the adult testis, it was specific to spermatocytes in stages IX and X of the cycle of the seminiferous epithelium. Five main immunoreactive proteins were detected using Western blot (220, 120, 90, 66, and 46 kDa). The 120-kDa protein was evident only in 20-day-old and older testes, whereas the 90-kDa band was present only in the 5- and 10-day-old testis. Leptin treatment induced phosphorylation of signal transducer and activator of transcription-3 in cultured seminiferous tubules from adult and 5-day-old testes. Our results show for the first time age- and stage-specific localization of a functional Ob-R in testicular germ cells. We hypothesize a direct role for leptin, through phosphorylation of signal transducer and activator of transcription-3, in proliferation and differentiation of germ cells, which may partially explain the infertility observed in leptin-deficient mice.

scholarly journals Differences in metabolomic profiles of male db/db and s/s, leptin receptor mutant mice

2012 ◽  
Vol 44 (6) ◽  
pp. 374-381 ◽  
Author(s):  
Nadia Saadat ◽  
Heidi B. IglayReger ◽  
Martin G. Myers ◽  
Peter Bodary ◽  
Smiti V. Gupta
Keyword(s):  
Mouse Models ◽  
Intracellular Signaling ◽  
Leptin Receptor ◽  
Deuterium Oxide ◽  
Active Form ◽  
Mutant Mice ◽  
Metabolic Effects ◽  
Proton Nuclear Magnetic Resonance ◽  
Resonance Spectroscopy ◽  
Signaling Domain

Leptin, a protein hormone secreted by adipose tissue, plays an important role in regulating energy metabolism and the immune response. Despite similar extremes of adiposity, mutant mouse models, db/db, carrying spontaneous deletion of the active form of the leptin receptor (LEPR-B) intracellular signaling domain, and the s/s, carrying a specific point mutation leading to a dysfunctional LEPR-B-STAT3 signaling pathway, have been shown to have robust differences in glucose homeostasis. This suggests specific effects of leptin, mediated by non-STAT3 LEPR-B pathways. Differences in the LEPR-B signaling pathways in these two LEPR-B mutant mice models are expected to lead to differences in metabolism. In the current study, the hypothesized differences in metabolism were investigated using the metabolomics approach. Proton nuclear magnetic resonance spectroscopy (1HNMR) was conducted on 24 h urine samples in deuterium oxide using a 500 MHz instrument at 25°C. Principle Component Analysis showed clear separation of urine NMR spectra between the groups ( P < 0.05). The CHENOMX metabolite database was used to identify several metabolites that differed between the two mouse models. Significant differences ( P < 0.05) in metabolites associated with the glycine, serine, and homocysteine metabolism were observed. The results demonstrate that the metabolomic profile of db/db and s/s mice are fundamentally different and provide insight into the unique metabolic effects of leptin exerted through non-STAT3 LEPR-B pathways.

scholarly journals Leptin influences the excitability of area postrema neurons

2016 ◽  
Vol 310 (5) ◽  
pp. R440-R448 ◽  
Author(s):  
Pauline M. Smith ◽  
Paulina Brzezinska ◽  
Fabien Hubert ◽  
Andrea Mimee ◽  
Donald H. Maurice ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Leptin Receptor ◽  
Area Postrema ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Energy Status ◽  
Rt Pcr ◽  
Intracellular Signaling Pathways ◽  
Cell Current ◽  
Camp Levels

The area postrema (AP) is a circumventricular organ with important roles in central autonomic regulation. This medullary structure has been shown to express the leptin receptor and has been suggested to have a role in modulating peripheral signals, indicating energy status. Using RT-PCR, we have confirmed the presence of mRNA for the leptin receptor, ObRb, in AP, and whole cell current-clamp recordings from dissociated AP neurons demonstrated that leptin influenced the excitability of 51% (42/82) of AP neurons. The majority of responsive neurons (62%) exhibited a depolarization (5.3 ± 0.7 mV), while the remaining affected cells (16/42) demonstrated hyperpolarizing effects (−5.96 ± 0.95 mV). Amylin was found to influence the same population of AP neurons. To elucidate the mechanism(s) of leptin and amylin actions in the AP, we used fluorescence resonance energy transfer (FRET) to determine the effect of these peptides on cAMP levels in single AP neurons. Leptin and amylin were found to elevate cAMP levels in the same dissociated AP neurons (leptin: % total FRET response 25.3 ± 4.9, n = 14; amylin: % total FRET response 21.7 ± 3.1, n = 13). When leptin and amylin were coapplied, % total FRET response rose to 53.0 ± 8.3 ( n = 6). The demonstration that leptin and amylin influence a subpopulation of AP neurons and that these two signaling molecules have additive effects on single AP neurons to increase cAMP, supports a role for the AP as a central nervous system location at which these circulating signals may act through common intracellular signaling pathways to influence central control of energy balance.

scholarly journals Hyperphagia and Obesity in Female Mice Lacking Tissue Inhibitor of Metalloproteinase-1

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1697-1704 ◽  
Author(s):  
Isabelle Gerin ◽  
Gwendolyn W. Louis ◽  
Xuan Zhang ◽  
Tyler C. Prestwich ◽  
T. Rajendra Kumar ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Food Intake ◽  
Matrix Metalloproteinases ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Signal Transducer ◽  
Altered Expression ◽  
Total Body ◽  
Transcription 3

Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1&lt;tm1Pds&gt; mice, which have a null mutation in Timp1 (Timp1−/−), we observed that females exhibit increased body weight by 3 months of age due to increased total body lipid and adipose tissue. Whereas Timp1−/− mice have increased size and number of adipocytes, they also display increased food intake despite hyperleptinemia, suggesting that alterations in hypothalamic leptin action or responsiveness may underlie their weight gain. Indeed, leptin promotes the expression of Timp1 mRNA in the hypothalamus, and leptin signaling via signal transducer and activator of transcription-3 mediates the expression of hypothalamic Timp1. Furthermore, Timp1−/− mice demonstrate increased food intake and altered expression of certain hypothalamic neuropeptide genes prior to elevated weight gain. Thus, whereas previous data suggested roles for matrix metalloproteinases and TIMPs in the regulation of adipose tissue, these data reveal that Timp1 mRNA is induced by leptin in the hypothalamus and that expression and action of Timp1 contributes to the regulation of feeding and energy balance.

scholarly journals Specific Physiological Roles for Signal Transducer and Activator of Transcription 3 in Leptin Receptor-Expressing Neurons

2008 ◽  
Vol 22 (3) ◽  
pp. 751-759 ◽  
Author(s):  
Merisa L. Piper ◽  
Elizabeth K. Unger ◽  
Martin G. Myers ◽  
Allison W. Xu
Keyword(s):  
Leptin Receptor ◽  
Signal Transducer ◽  
Transcription 3

scholarly journals The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Gwen V. Childs ◽  
Noor Akhter ◽  
Anessa Haney ◽  
Mohsin Syed ◽  
Angela Odle ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Leptin Receptor ◽  
Lipolytic Activity ◽  
Growth Curves ◽  
Mutant Mice ◽  
Pituitary Cells ◽  
Leptin Receptors ◽  
Gh Cells ◽  
And Function ◽  
Transcription 3

Abstract Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new animal model in which exon 17 of the leptin receptor (Lepr) protein was selectively deleted in somatotropes by Cre-loxP technology. Organ genotyping confirmed the recombination of the floxed LepR allele only in the pituitary. Deletion mutant mice showed a 72% reduction in pituitary cells bearing leptin receptor (LEPR)-b, a 43% reduction in LEPR proteins and a 60% reduction in percentages of immunopositive GH cells, which correlated with reduced serum GH. In mutants, LEPR expression by other pituitary cells was like that of normal animals. Leptin stimulated phosphorylated Signal transducer and activator of transcription 3 expression in somatotropes from normal animals but not from mutants. Pituitary weights, cell numbers, IGF-I, and the timing of puberty were not different from control values. Growth curves were normal during the first 3 months. Deletion mutant mice became approximately 30–46% heavier than controls with age, which was attributed to an increase in fat mass. Serum leptin levels were either normal in younger animals or reflected the level of obesity in older animals. The specific ablation of the Lepr exon 17 gene in somatotropes resulted in GH deficiency with a consequential reduction in lipolytic activity normally maintained by GH and increased adiposity.

Mechanisms of Amylin/Leptin Synergy in Rodent Models

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Victoria F. Turek ◽  
James L. Trevaskis ◽  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
Boman Irani ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Leptin Receptor ◽  
Therapeutic Potential ◽  
Ventromedial Hypothalamus ◽  
Signal Transducer ◽  
Leptin Signaling ◽  
Reduced Body ◽  
Epididymal Fat ◽  
Transcription 3

Abstract The present studies aimed to identify mechanisms contributing to amylin/leptin synergy in reducing body weight and adiposity. We reasoned that if amylin/leptin harnessed complementary neuronal pathways, then in the leptin-sensitive state, amylin should augment leptin signaling/binding and that in the absence of endogenous amylin, leptin signaling should be diminished. Amylin (50 μg/kg, ip) amplified low-dose leptin-stimulated (15 μg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 μg/kg · d) or leptin (125 μg/kg · d) infusion to lean rats decreased 28-d food intake (14 and 10%, respectively), body weight (amylin by 4.3%, leptin by 4.9%), and epididymal fat (amylin by 19%, leptin by 37%). Amylin/leptin co-infusion additively decreased food intake (by 26%) and reduced body weight (by 15%) and epididymal fat (by 78%; all P &lt; 0.05 vs. all groups) in a greater than mathematically additive manner, consistent with synergy. Amylin increased leptin binding within the ventromedial hypothalamus (VMN) by 35% and dorsomedial hypothalamus by 47% (both P &lt; 0.05 vs. vehicle). Amylin/leptin similarly increased leptin binding in the VMN by 40% and ARC by 70% (P &lt; 0.05 vs. vehicle). In amylin-deficient mice, hypothalamic leptin receptor mRNA expression was reduced by 50%, leptin-stimulated phosphorylated signal transducer and activator of transcription-3 within ARC and VMN was reduced by 40%, and responsiveness to leptin’s (1 mg/kg · d for 28 d) weight-reducing effects was attenuated (all P &lt; 0.05 vs. wild-type controls). We suggest that amylin/leptin’s marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways and further point to the integrated neurohormonal therapeutic potential of amylin/leptin agonism in obesity.

scholarly journals Neither Signal Transducer and Activator of Transcription 3 (STAT3) or STAT5 Signaling Pathways Are Required for Leptin's Effects on Fertility in Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2434-2445 ◽  
Author(s):  
Amritha V. Singireddy ◽  
Megan A. Inglis ◽  
Wieteke A. Zuure ◽  
Joon S. Kim ◽  
Greg M. Anderson
Keyword(s):  
Body Weight ◽  
Intracellular Signaling ◽  
Leptin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Weight Regulation ◽  
Body Weight Regulation ◽  
Subsequent Fertility ◽  
Estrous Cyclicity ◽  
Puberty Onset

Abstract The hormone leptin is critical for the regulation of energy balance and fertility. The long-form leptin receptor (LepR) regulates multiple intracellular signaling cascades, including the classic Janus kinase-signal transducer and activator of transcription (STAT) pathways. Previous studies have shown that deletion of STAT3 or the closely related STAT5 from the brain results in an obese phenotype, but their roles in fertility regulation are not clear. This study tested whether STAT3 and STAT5 pathways of leptin signaling are required for fertility, and whether absence of one pathway might be compensated for by the other in a redundant manner. A Cre-loxP approach was used to generate 3 models of male and female transgenic mice with LepR-specific deletion of STAT3, STAT5, or both STAT3 and STAT5. Body weight, puberty onset, estrous cyclicity, and fertility were measured in all knockout (KO) mice and their control littermates. Knocking out STAT3 or both STAT3 and 5 from LepR expressing cells, but not STAT5 alone, led to significant increase in body weight. All STAT3 and STAT5 single KO mice exhibited normal puberty onset and subsequent fertility compared to their control littermates. Surprisingly, all STAT3 and STAT5 double KO mice also exhibited normal puberty onset, estrous cyclicity, and fertility, although they had severely disrupted body weight regulation. These results suggest that, although STAT3 signaling is crucial for body weight regulation, neither STAT3 nor STAT5 is required for the regulation of fertility by leptin. It remains to be determined what other signaling molecules mediate this effect of leptin, and whether they interact in a redundant manner.

scholarly journals Feedback Inhibition of Leptin Receptor/Jak2 Signaling via Tyr1138 of the Leptin Receptor and Suppressor of Cytokine Signaling 3

2005 ◽  
Vol 19 (4) ◽  
pp. 925-938 ◽  
Author(s):  
Sarah L. Dunn ◽  
Marie Björnholm ◽  
Sarah H. Bates ◽  
Zhibin Chen ◽  
Matthew Seifert ◽  
...  
Keyword(s):  
Rna Interference ◽  
Leptin Receptor ◽  
Feedback Inhibition ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity ◽  
Transcription 3

Abstract Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

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