Role of Gq/11-alpha in metabolic regulation

到目前为止，我们已经使用Sim1-cre转基因小鼠在下丘脑室旁核(PVN)产生了GQ/11-α缺陷小鼠。这些小鼠出现严重肥胖，并伴有吞噬过度，但能量消耗或葡萄糖代谢没有变化。他们还表明，黑素皮质素4受体(MC4R)激动剂(MTII)严重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-α。这些发现表明，MC4R通过在下丘脑室旁核通过GQ/11-α途径抑制食物摄取。将AAV-cre直接注射到GQ-FLOXED/G11-α基因缺陷小鼠的PVN中也得到了类似的结果。相反，MC4R对PVN的心血管效应是通过Gs-α介导的。此外，GQ/11-α信号在下丘脑-垂体-肾上腺轴的调节中起重要作用。我们目前正在研究各种人类MC4R突变，以检查它们的信号特性和导致肥胖的机制，以及允许MC4R通过GQ/11-α发出信号的生化因素。 我们还使用aP2-cre和脂联素-cre转基因小鼠敲除了脂肪组织中的GQ/11-α，没有发现主要的表型，这与我们使用同样的cre转基因系(DK043316)敲除Gs-α后所看到的情况形成了鲜明的对比。我们还在肝脏中敲除了GQ/11-α。一项研究表明，GQ/11信号对软骨细胞的分化也很重要。初步结果还表明，G11-α基因敲除小鼠对饮食诱导的肥胖具有抵抗力。 有证据表明，下丘脑背内侧的GQ/11-α信号对能量平衡，特别是对能量消耗的刺激和小鼠白色脂肪组织的褐化很重要，尽管这些影响不太可能是MC4R信号的下游。 我们有证据表明，肥胖相关的人黑素皮质素受体MC4R突变通过Gs/cAMP在体内和体外都具有正常信号，但仍会导致过度吞噬和肥胖，这意味着另一条途径，很可能是Gq/11。体外研究证实，该突变在Gq/11信号中存在特异性缺陷。

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.