Role of Gq/11-alpha in metabolic regulation

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

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.