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，我们使用SIM1-CRE转基因小鼠在下丘脑（PVN）的室室核中产生了具有GQ/11-Alpha缺乏症的小鼠。这些小鼠会出现与肉质相关的严重肥胖症，而能量消耗或葡萄糖代谢没有变化。它们还显示出黑色素素4受体（MC4R）激动剂（MTII）急性抑制食物摄入的能力。我们确认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途径抑制食物摄入量。通过将AAV-CRE直接注入GQ-氟/G11-α缺陷小鼠的PVN获得了类似的结果。相反，MC4R在PVN中的心血管效应是由GS-Alpha介导的。此外，GQ/11-Alpha信号在调节下丘脑 - 垂体 - 肾上腺轴上很重要。我们目前正在研究各种人类MC4R突变，以检查其信号传导特性以及它们导致肥胖的机制，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转基因小鼠在脂肪组织中淘汰了脂肪组织中的GQ/11-α，与使用同样的Cre-transgenic line（DK043316）敲除GS-Alpha后看到的相比，没有看到主要表型。我们还在肝脏中淘汰了GQ/11-Alpha。在协作中，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-Alpha基因敲除小鼠对饮食诱导的肥胖症具有抗性。有证据表明，背侧下丘脑中的GQ/11-α信号在能量平衡中很重要，特别是刺激能量消耗和小鼠白色脂肪组织的褐变，尽管这些作用不太可能在MC4R信号的下游。我们有证据表明，与肥胖相关的人黑色皮质素受体MC4R突变体通过体内GS/CAMP进行正常信号传导，并且体外会导致肥大和肥胖，这意味着替代途径，很可能是GQ/11。体外研究证实，该突变在GQ/11信号传导中具有特定的缺陷。