Central Inhibition of HDAC6 Re-Sensitizes Leptin Signaling During Obesity to Induce Profound Weight Loss
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252779 | GEO | 2024/01/09
REPOSITORIES: GEO
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Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.
2021-09-09 | PXD020959 | Pride
Project description:Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR (db/db) and leptin (ob/ob) are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4, a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO cite, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Surprisingly, exogenous ANGPTL4 treatment not only promoted HO, but facilitated the transformation from white to brown adipose tissue in mice. These findings identify ANGPTL4 as a novel ligand for LepR to stimulate HO and regulate fat metabolism.
2024-07-03 | PXD043087 | Pride
Project description:Introduction: Obesity and overweight affect more than one third of the world population, and are significant risk factors for type II diabetes, cardiovascular disease and cancer. Common obesity is usually accompanied by hyperleptinemia and leptin resistance. Purpose: Here, we investigate the molecular pathways underlying the effects of HDAC6 inhibition in reversing diet-induced obesity and interrogate potential pathways that link HDAC6 with leptin receptor signaling by conducting whole transcriptome analysis in white adipose tissues of the diet-induced obese mice that were treated with tubastatin A (an HDAC6-specific inhibitor) and in fat-specific HDAC6 knockout mice. Methods: Male 4-5 week-old C57B/6J wild type mice were fed with high fat diet for 16-20 weeks to generate diet-induced obese (DIO) mice. Around 28 weeks of age, mice were treated with daily ip injections of either tubastatin A-HCl (TubA, 25 mg/kg) or vehicle for four days. We probed the whole transcriptome in epididymal white adipose tissue (eWAT), and inguinal white adipose tissue (iWAT) following vehicle or TubA administration (eWAT.Veh, eWAT.TubA, iWAT.Veh, iWAT.TubA groups). In a separate cohort, DIO HDAC6 global knockout mice were treated with vehicle (Veh group) or TubA (TubA group). eWAT was excised for RNA extraction. In the third cohort, adipose tissue specific HDAC6 knockout mice were generated crossing adiponectin-Cre mice with HDAC6-floxed mice. These fat specific HDAC6 KO mice (AdKO) and their adiponectin-Cre controls (AdCre) were treated with vehicle for five weeks. eWAT was excised for RNA extraction.Total RNA samples from each tissue were extracted using Trizol. RNA Sequencing for the wild-type iWAT and eWAT samples from vehicle or TubA-treated mice was performed by the University of Michigan Sequencing Core, using the Illumina Hi-Seq 4000 platform. RNA sequencing for the other samples were conducted by Novogene, NovaSeq 6000 PE150, HiSeq SE50 platform. The following bioinformatics analysis have been conducted by Novogene: 1. Data Quality Control: filtering reads containing adapter or with low quality. 2. Statistics Analysis of Data Production and Quality. 3. Mapping Reads to Reference Genome. 4. Gene Expression Quantification. 5. Correlation analysis (For biological replicates only). 6. Differential Expression Analysis (two or more groups of samples). 7. GO Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 8. KEGG Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 9. GSEA Enrichment Analysis of Expressed Genes (two or more groups of samples). 10. Protein Protein Interaction Analysis. 11. Reactome Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse samples). 12. Oncogene Functional Annotation analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse sample). Results: Inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent anti-obesity agents, and leptin sensitizers. HDAC6 inhibitor TubA suppresses food intake and reduce obesity, in an HDAC6-dependent manner, resulting in up to fifty percent decrease in fat mass in DIO mice accompanied by significantly reduced hepatic steatosis and improved systemic glucose homeostasis. Conclusions: Mechanistically, peripheral -but not central- inhibition of HDAC6 confers central leptin sensitivity, and the anti-obesity effect of TubA is significantly attenuated in animals defective in the central leptin-melanocortin circuitry, including the db/db and MCR4 KO mice.
2021-12-05 | GSE190156 | GEO
Project description:Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. These SPCIL33cKO mice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKO mice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+ IL33+SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.
2023-12-12 | GSE227493 | GEO
Project description:The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that trigger the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive elementâ??binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproductionâ??Crtc1-/- mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice; leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptinâ??s effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility. Experiment Overall Design: Mice were fasted overnight for 18h and refed for 6h. Hypothalami were obtained from 3 wild-type and 3 Crtc1 knockout mice. Total RNA was isolated from each sample and equal amounts from each sample were pooled for the microarray.
2008-10-25 | E-GEOD-12209 | biostudies-arrayexpress
Project description:The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that trigger the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element–binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction—Crtc1-/- mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice; leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin’s effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.
2008-09-04 | GSE12209 | GEO
Project description:Introduction: Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis and ex vivo insulin secretion and Ca2+ dynamics. However, Lepr removal from neither alpha nor beta cells mimics this result. Moreover, scRNAseq data has revealed an enrichment of LEPR in human islet delta cells. Methods: We confirmed LEPR upregulation in human delta cells by performing RNAseq on fixed, sorted beta and delta cells. We then used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. Results: Ablation of Lepr within mouse delta cells did not change glucose homeostasis or insulin secretion, whether mice were fed a chow or high-fat diet. We further show, using a publicly available scRNAseq dataset, that islet cells expressing Lepr lie within endothelial cell clusters. Conclusions: In mice, leptin does not influence beta-cell function through delta cells.
2023-10-02 | GSE243984 | GEO
Project description:In contrast to light-dependent entrainment of the central circadian pacemaker, the molecular and neural underpinnings of entrainment by non-photic cues, such as food, remain unclear. Using single-nucleus RNA-sequencing, we identified a leptin receptor (LepR) positive neuronal population in the dorsomedial hypothalamus (DMH) that is responsive to scheduled feeding (SF). During SF, DMH LepR neuron activity precedes an impending meal. Mis-timed exogenous leptin administration or chemogenetic activation of DMH LepR neurons inhibits both neuronal and behavioral food anticipatory activities. Further, repetitive chemogenetic activation of DMH LepR neurons partitions a secondary bout of circadian locomotor activity in phase with the stimulation. This work places DMH LepR neurons as an essential integrator of food entrainment, and positions leptin as a critical central mediator of this circadian response.
2023-06-14 | GSE211757 | GEO
Project description:Leptin binding to the leptin receptor (LepR) causes rapid signaling to the nucleus. We investigated the early (2 hr) transcriptional response to acute leptin injectio (intracerebroventricular) in the preoptic area/hypothalamus/pituitary of juvenile Xenopus laevis frogs. Frogs were given i.c.v. injections of 0.6% saline or recombinant X. laevis leptin (rxLeptin; 20 ng/g BW) and 2 hrs later killed and the preoptic area/hypothalamus/pituitary dissected.
2014-08-05 | E-GEOD-60053 | biostudies-arrayexpress
Project description:Leptin binding to the leptin receptor (LepR) causes rapid signaling to the nucleus. We investigated the early (2 hr) transcriptional response to acute leptin injection (intracerebroventricular) in the preoptic area/hypothalamus/pituitary of Xenopus tadpoles.
2017-03-31 | GSE97243 | GEO