Leptin-mediated control of body weight by a conserved population of Glp1r-expressing neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723342 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14289030_1.fastq.gz | Fastqsanger.gz | |||
| SRR14289030_2.fastq.gz | Fastqsanger.gz | |||
| SRR14289033_1.fastq.gz | Fastqsanger.gz | |||
| SRR14289033_2.fastq.gz | Fastqsanger.gz | |||
| SRR14289034_1.fastq.gz | Fastqsanger.gz |
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Project description:Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes.Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a novel compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.
2024-02-29 | GSE252186 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-14 | GSE172463 | GEO
Project description:The purpose of this study was to identify leptin target genes and subsequent pathways correlated with leptin-mediated weight loss. We utilized the microarray technology to compare two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We report here the impact of central and peripheral administration of leptin on food intake, body weight and body fat composition in ob/ob mice. We also report hepatic gene expression changes caused by central versus peripheral leptin administration. Keywords: comparison
2010-11-10 | GSE20878 | GEO
Project description:The purpose of this study was to identify leptin target genes and subsequent pathways correlated with leptin-mediated weight loss. We utilized the microarray technology to compare two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We report here the impact of central and peripheral administration of leptin on food intake, body weight and body fat composition in ob/ob mice. We also report hepatic gene expression changes caused by central versus peripheral leptin administration. Keywords: comparison Leptin deficient (ob/ob) mice were continuously administered leptin over 12-days using central (intracerebroventricular) or peripheral (subcutaneous) route of administration. Liver RNA was extracted and hybridized to Illumina microarrays and gene expression data was analyzed. The global gene expression profiles were compared after the central and peripheral leptin treatments in ob/ob mice and C57BL6 mice were used for the baseline gene expression.
2010-11-10 | E-GEOD-20878 | biostudies-arrayexpress
Project description:A Negative Feedback Loop Between TET2 and Leptin in Adipocyte Regulates Body Weight
| PRJNA1058461 | ENA
Project description:Leptin resistance during excess weigh gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of Leptin receptor b (LepR) signaling during obesity is still elusive. Here we report that histone deactylase 6 (HDAC6) interacts with LepR, reducing the latter’s activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of obese mice with blood brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to a potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in AgRP-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors result in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally-, but not peripherally-acting HDAC6 inhibitors as potent leptin-sensitizers and anti-obesity agents.
2024-01-09 | GSE252779 | GEO
Project description:Infertility is a growing global health concern affecting millions of couples worldwide. Both overweight and underweight individuals face reproductive issues, resulting in infertility. Due to small size and short life, mice are not necessarily suitable animal models for human infertility. While, pigs having large size, anatomical and physiological similarities with human are considered as more ideal animal model of human disease. Leptin is a well-known adipokine that serves as an endocrine signal between adiposity and fertility. However, the exact mechanisms underlying leptin's effects on reproductive function remain unclear. To shed light on this, our study focused on pigs genetically engineered to overexpress leptin. These leptin-overexpressing pigs exhibited several reproductive abnormalities, including reduced body weight and size, decreased back fat thickness, and displayed late onset of puberty, and irregular estrous behavior characterized by increased inter-estrous interval and more breeding attempts until pregnancy. This reproductive impairment in leptin pigs was followed by hormonal imbalances and altered steroidogenesis. Bulk RNA sequencing of the ovaries revealed neutrophilic infiltration followed by upregulation of inflammation related genes. To gain a deeper understanding of the cellular levels, we employed single-nucleus RNA sequencing (snRNA-seq), and found that leptin overexpression triggered immune response, suppressed follicle development and luteinization, imposing metabolism dysfunction and hormone imbalance in ovary. Further, trends of phenotypical infertility symptoms and endocrine changes in underweight female patients mirrored the alterations observed in our leptin pigs. These findings suggest that leptin-overexpressing pigs could serve as a valuable animal model for studying infertility and investigating potential therapeutic interventions.
2023-07-17 | GSE237153 | GEO
Project description:Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, very few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we show that by combining FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic approaches (RNA-seq, ChIP-seq, ATAC-seq), we can provide a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. Further demonstrating the robustness of our leptin-response neuron regulome, we functionally characterize a novel enhancer near Socs3, a leptin response-associated transcription factor. Combined, our results provide a comprehensive map of active genomic regions in leptin-responsive neurons and present a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus.
2019-04-01 | GSE112125 | GEO
Project description:Variants of the G protein-coupled receptor 75 (GPR75) are associated with lower BMI in large-scale human exome sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75 knockout (Gpr75–/–) mice. Gpr75–/– mice displayed reduced food intake under a high-fat diet (HFD), and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag tagged Gpr75 knock-in (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants with lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in Leptin ob mice and Adenylate cyclase 3 (Adcy3) mutant mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake.
2024-08-13 | GSE254239 | GEO
Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.
2011-04-29 | E-GEOD-16790 | biostudies-arrayexpress