Role of Gq/11-alpha in metabolic regulation

Gq/11-alpha 在代谢调节中的作用

基本信息

批准号：
10697817
负责人：
Lee Weinstein
金额：
$ 77.02万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697817
关键词：
Acute Adipose tissue Agonist Alleles Biochemical Central Nervous System Chondrocytes Collaborations Cyclic AMP Defect Eating Energy Metabolism Enterobacteria phage P1 Cre recombinase Enzymes GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genes Goals Hormones Human Hyperphagia Hypothalamic structure In Vitro Knock-out Knockout Mice Lead Liver LoxP-flanked allele Mediating Melanocortin 4 Receptor Melanocortin 4 receptor mutation Metabolic Morbid Obesity Mus Mutation Neurotransmitters Obesity Pathway interactions Peripheral Phenotype Phospholipase C Play Property Receptor Signaling Regulation Resistance Role Signal Transduction Tissues Transgenes Transgenic Mice Transgenic Organisms adiponectin cardiovascular effects diet-induced obesity energy balance extracellular glucose metabolism hypothalamic-pituitary-adrenal axis in vivo melanocortin receptor mutant paraventricular nucleus promoter receptor virtual

项目摘要

To date we have generated mice with Gq/11-alpha deficiency in the paraventricular nucleus of the hypothalamus (PVN) using Sim1-cre transgenic mice. These mice develop severe obesity associated with hyperphagia with no change in energy expenditure or in glucose metabolism. They also show a defect in the ability of a melanocortin 4 receptor (MC4R) agonist (MTII) to inhibit food intake acutely. We confirmed that MC4R can activate Gq/11-alpha in PVN. These findings suggest that MC4R inhibits food intake via a Gq/11-alpha pathway in the PVN. Similar results were obtained by injecting AAV-cre directly into PVN of Gq-floxed/G11-alpha deficient mice. In contrast the cardiovascular effects of MC4R in PVN are mediated by Gs-alpha. Moreover, Gq/11-alpha signaling is important in regulation of the hypothalamic-pituitary-adrenal axis. We are presently studying various human MC4R mutations to examine their signaling properties and the mechanisms by which they lead to obesity, as well as the biochemical factors involved in allowing MC4R to signal via Gq/11-alpha. We also knocked out Gq/11-alpha in adipose tissue using aP2-cre and adiponectin-cre transgenic mice and see no major phenotype, in contrast to what we see after knocking out Gs-alpha using this same cre-transgenic line (DK043316). We are also knocking out Gq/11-alpha in liver. In a collaboration it was shown that Gq/11 signaling is also important for chondrocyte differentiation. Prelimary results also show that G11-alpha knockout mice are resistant to diet-induced obesity. Evidence shows that Gq/11-alpha signaling in the dorsomedial hypothalamus is important in energy balance, in particular stimulation of energy expenditure and in browning of white adipose tissue in mice, although these effects are unlikely to be downstream of MC4R signaling. We have evidence that an obesity-associated human melanocortin receptor MC4R mutant with normal signaling via Gs/cAMP in vivo and in vitro nevertheless leads to hyperphagia and obesity, implicating an alternate pathway, most likely Gq/11. In vitro studies have confirmed that this mutation has a specific defect in Gq/11 signaling.

迄今为止，我们已经使用 Sim1-cre 转基因小鼠培育出下丘脑室旁核 (PVN) 缺乏 Gq/11-α 的小鼠。这些小鼠出现与进食过多相关的严重肥胖，但能量消耗或葡萄糖代谢没有变化。它们还显示黑皮质素 4 受体 (MC4R) 激动剂 (MTII) 急剧抑制食物摄入的能力存在缺陷。我们证实 MC4R 可以激活 PVN 中的 Gq/11-alpha。这些发现表明 MC4R 通过 PVN 中的 Gq/11-alpha 途径抑制食物摄入。通过将 AAV-cre 直接注射到 Gq-floxed/G11-alpha 缺陷小鼠的 PVN 中也获得了类似的结果。相反，PVN 中 MC4R 的心血管作用是由 Gs-α 介导的。此外，Gq/11-α 信号传导对于下丘脑-垂体-肾上腺轴的调节也很重要。我们目前正在研究各种人类 MC4R 突变，以检查它们的信号传导特性和导致肥胖的机制，以及允许 MC4R 通过 Gq/11-alpha 发出信号的生化因素。我们还使用 aP2-cre 和脂联素-cre 转基因小鼠敲除脂肪组织中的 Gq/11-alpha，没有看到主要表型，这与我们使用相同的 cre 转基因系 (DK043316) 敲除 Gs-alpha 后看到的情况形成鲜明对比。我们还敲除肝脏中的 Gq/11-alpha。一项合作表明，Gq/11 信号传导对于软骨细胞分化也很重要。初步结果还表明，G11-α 基因敲除小鼠对饮食引起的肥胖具有抵抗力。有证据表明，下丘脑背内侧的 Gq/11-α 信号传导对于能量平衡很重要，特别是刺激能量消耗和小鼠白色脂肪组织褐变，尽管这些作用不太可能是 MC4R 信号传导的下游。我们有证据表明，与肥胖相关的人类黑皮质素受体 MC4R 突变体在体内和体外通过 Gs/cAMP 发出正常信号，但仍然会导致食欲过盛和肥胖，这表明存在替代途径，最有可能是 Gq/11。体外研究证实，该突变在 Gq/11 信号传导中存在特定缺陷。