Role of the TORC/CRTC Family of Coactivators in Energy Balance

描述(申请人提供)：葡萄糖和脂肪的动态平衡通常通过胰岛素敏感组织之间的激素和营养信号通路网络来维持。事实上，组织间沟通的中断通常与II型糖尿病有关，尽管触发这一过程的启动事件尚未被表征。最近的研究发现，肥胖可以刺激脂肪中cAMP反应因子CREB的磷酸化和激活；肥胖CREB活性缺陷的小鼠在饮食或遗传肥胖的背景下仍然对胰岛素敏感。目前的提案阐述了CREB共激活因子CRTC3在调节CREB在脂肪中的代谢效应中的重要性。提出了三个目标；在目标1中，将描述CRTC3基因中断使人对饮食诱导的肥胖产生胰岛素敏感性和抵抗的机制。将确定营养和饮食状况在引发CRTC3依赖的能量消耗、食物摄入量和体力活动变化方面的影响。并将探讨其他CRTC家族成员对监管的潜在贡献。在目标2中，将评估CRTC3通过对儿茶酚胺信号和脂肪形成的影响来调节能量消耗的相对重要性。在目标3中，将表征核小体重塑和脱乙酰酶复合体(NuRD)通过与CREB和CRTC3的关联而沉默cAMP反应基因的作用。这些研究将深入了解CREB：CRTC3通路在引发脂肪早期变化中的重要性，这些变化导致肥胖患者发生系统性胰岛素抵抗。

DESCRIPTION (provided by applicant): Glucose and lipid homeostasis are normally maintained through a network of hormonal and nutrient signaling pathways that operate between insulin sensitive tissues. Indeed, disruptions in inter-tissue communication are often associated with type II diabetes, although initiating events that trigger this process have not been characterized. In recent studies, obesity was found to stimulate the phosphorylation and activation of the cAMP responsive factor CREB in adipose; mice deficient in adiposity CREB activity remained insulin sensitive in the context of dietary or genetic obesity. The current proposal addresses the importance of the CREB coactivator CRTC3 in mediating the metabolic effects of CREB in adipose. Three Aims are proposed; In Aim 1, the mechanism by which disruption of the CRTC3 gene confers insulin sensitivity and resistance to diet induced obesity will be characterized. Effects of nutritional and dietary status in triggering CRTC3-dependent changes in energy expenditure, food intake, and physical activity will be determined. And potential regulatory contributions from other CRTC family members will be explored. In Aim 2, the relative importance of CRTC3 in modulating energy expenditure through its effects on catecholamine signaling and adipogenesis will be evaluated. In Aim 3, the role of the nucleosome remodeling and deacetylase complex (NuRD) in silencing cAMP responsive genes through an association with CREB and CRTC3 will be characterized. These studies will provide insight into the importance of the CREB:CRTC3 pathway in triggering early changes in adipose that lead to the development of systemic insulin resistance in obesity.