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.

scholarly journals Ghrelin Restoration of Function In Vitro in Somatotropes from Male Mice Lacking the Janus Kinase (JAK)-Binding Site of the Leptin Receptor

Endocrinology ◽  
2013 ◽  
Vol 154 (4) ◽  
pp. 1565-1576 ◽  
Author(s):  
Mohsin Syed ◽  
Michael Cozart ◽  
Anessa C. Haney ◽  
Noor Akhter ◽  
Angela K. Odle ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Janus Kinase ◽  
Pituitary Cells ◽  
Male Mice ◽  
Control Male ◽  
Leptin Receptors ◽  
Gh Secretion ◽  
Gh Cells ◽  
Signaling Domain

Abstract Deletion of the signaling domain of leptin receptors selectively in somatotropes, with Cre-loxP technology, reduced the percentage of immunolabeled GH cells and serum GH. We hypothesized that the deficit occurred when leptin's postnatal surge failed to stimulate an expansion in the cell population. To learn more about the deficiency in GH cells, we tested their expression of GHRH receptors and GH mRNA and the restorative potential of secretagogue stimulation in vitro. In freshly plated dissociated pituitary cells from control male mice, GHRH alone (0.3 nM) increased the percentage of immunolabeled GH cells from 27 ± 0.05% (vehicle) to 42 ± 1.8% (P < .002) and the secretion of GH 1.8–3×. Deletion mutant pituitary cells showed a 40% reduction in percentages of immunolabeled GH cells (16.7 ± 0.4%), which correlated with a 47% reduction in basal GH levels (50 ng/mL control; 26.7 ng/mL mutants P = .01). A 50% reduction in the percentage of mutant cells expressing GHRH receptors (to 12%) correlated with no or reduced responses to GHRH. Ghrelin alone (10 nM) stimulated more GH cells in mutants (from 16.7–23%). When added with 1–3 nM GHRH, ghrelin restored GH cell percentages and GH secretion to levels similar to those of stimulated controls. Counts of somatotropes labeled for GH mRNA confirmed normal percentages of somatotropes in the population. These discoveries suggest that leptin may optimize somatotrope function by facilitating expression of membrane GHRH receptors and the production or maintenance of GH stores.

Lack of Sleep and Activity May Contribute to Adult-Onset Obesity in Deletion Mutant Mice Lacking Leptin Receptors in Pituitary Somatotropes

2011 ◽  
pp. P2-341-P2-341
Author(s):  
Noor Akhter ◽  
Angela K Odle ◽  
Michael A Cozart ◽  
Mohsin M Syed ◽  
Anessa C Haney ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Mutant Mice ◽  
Adult Onset ◽  
Leptin Receptors ◽  
Lack Of Sleep

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 The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jun Deng ◽  
Qian Chen ◽  
Zhian Chen ◽  
Kaili Liang ◽  
Xin Gao ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Serum Levels ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Vaccine Failure ◽  
Vaccine Responses ◽  
Follicular Helper ◽  
B Virus ◽  
And Function ◽  
Metabolic Hormone

AbstractFollicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

The relationship between BMI, leptin, leptin receptors (LepR) and Foxp3+ Tregs cells in women with asthma

2016 ◽  
Vol 51 (4) ◽  
pp. 277-284
Author(s):  
Łukasz Kraszula ◽  
Makandjou-Ola Eusebio ◽  
Anna Jasińska ◽  
Maciej Kupczyk ◽  
Piotr Kuna ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Leptin Receptor ◽  
Control Group ◽  
Soluble Receptor ◽  
Leptin Receptors ◽  
Global Initiative For Asthma ◽  
Moderate Disease ◽  
Global Initiative ◽  
And Control ◽  
The Relationship

The aim of this study was evaluation whether there is an association between BMI, leptin and its soluble receptor, the expression of FoxP3 in CD4+ pTreg in women with severe asthma. Materials and methods. The study included thirty women with asthma: 17 patients with severe and 13 with mild-moderate disease. The control group comprised of 25 healthy women. Asthma was diagnosed in accordance with the Global Initiative For Asthma guidelines (GINA 2014). The phenotype of CD4+CD25highCD127lowFoxp3+CD152+ cells was evaluated by multicolor flow cytometry. The concentration of leptin and its soluble receptor were determined using an immunoenzymatic method (ELISA). Results. It has been shown significantly increased leptin concentration in the group of women with severe asthma compared with mild-moderate asthma and control group (p <0.05). The concentration of the leptin receptor significantly increased (p <0.05) in women with severe asthma compared with control group. There were no differences in percentage of CD4+FoxP3+ and CD4+CD25highCD127low- FoxP3+CD152+ subsets after leptin stimulation in all tested groups. Conclusions. Our results don’t confirm the direct effect of leptin on the CD4+ pTreg cells and the expression of FoxP3 in these cells, in tested groups.

scholarly journals Shengmai San Alleviates Diabetic Cardiomyopathy Through Improvement of Mitochondrial Lipid Metabolic Disorder

2018 ◽  
Vol 50 (5) ◽  
pp. 1726-1739 ◽  
Author(s):  
Jing Tian ◽  
Wenzhu Tang ◽  
Ming Xu ◽  
Chen Zhang ◽  
Pei Zhao ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Leptin Receptor ◽  
Myocardial Hypertrophy ◽  
Oxphos Complex ◽  
H9c2 Cardiomyocytes ◽  
Mitochondrial Lipid ◽  
And Function ◽  
Shengmai San

Background/Aims: Shengmai San (SMS), prepared from Panax ginseng, Ophiopogon japonicus, and Schisandra chinensisin, has been widely used to treat ischemic disease. In this study, we investigated whether SMS may exert a beneficial effect in diabetic cardiomyopathy through improvement of mitochondrial lipid metabolism. Methods: A leptin receptor-deficient db/db mouse model was utilized, and lean age-matched C57BLKS mice served as non-diabetic controls. Glucose and lipid profiles, myocardial structure, dimension, and function, and heart weight to tibial length ratio were determined. Myocardial ultrastructural morphology was observed with transmission electron microscopy. Protein expression and activity of oxidative phosphorylation (OXPHOS) complex were assessed using western blotting and microplate assay kits. We also observed cellular viability, mitochondrial membrane potential, OXPHOS complex activity, and cellular ATP level in palmitic acid-stimulated H9C2 cardiomyocytes. Changes in the sirtuin (SIRT1)/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway and mitochondrial uncoupling signaling were assessed using western blotting and quantitative real-time PCR. Results: Leptin receptor-deficient db/db mice exhibit obesity, hyperglycemia, and hyperlipidemia, accompanied by distinct myocardial hypertrophy and diastolic dysfunction. SMS at a dose of 3 g/kg body weight contributed to a recovery of diabetes-induced myocardial hypertrophy and diastolic dysfunction. SMS administration led to an effective restoration of mitochondrial structure and function both in vivo and in vitro. Furthermore, SMS markedly enhanced SIRT1 and p-AMPKα protein levels and decreased the expression of acetylated-PGC-1α and uncoupling protein 2 protein. SMS also restored the depletion of NRF1 and TFAM levels in diabetic hearts and H9C2 cardiomyocytes. Conclusion: The results indicate that SMS may alleviate diabetes-induced myocardial hypertrophy and diastolic dysfunction by improving mitochondrial lipid metabolism.

scholarly journals An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum

2021 ◽  
Vol 15 ◽  
Author(s):  
Esther Suk King Lai ◽  
Hisako Nakayama ◽  
Taisuke Miyazaki ◽  
Takanobu Nakazawa ◽  
Katsuhiko Tabuchi ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Synapse Formation ◽  
Single Point ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Single Point Mutation ◽  
Synapse Elimination ◽  
Wild Type ◽  
Post Mortem Brain ◽  
And Function

Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10–15 (P10–15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.

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.

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