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

描述（由申请方提供）：葡萄糖和脂质稳态通常通过在胰岛素敏感组织之间运行的激素和营养信号通路网络来维持。事实上，组织间通讯的中断通常与II型糖尿病相关，尽管触发该过程的起始事件尚未被表征。在最近的研究中，发现肥胖刺激磷酸化和激活的cAMP反应因子CREB在脂肪;小鼠缺乏肥胖CREB活性保持胰岛素敏感的饮食或遗传性肥胖的背景下。目前的建议解决了CREB辅激活剂CRTC 3在介导CREB在脂肪中的代谢作用的重要性。提出了三个目标;在目的1中，将表征CRTC 3基因的破坏赋予胰岛素敏感性和对饮食诱导的肥胖的抗性的机制。将确定营养和饮食状态在触发能量消耗、食物摄入和体力活动的CRTC 3依赖性变化方面的影响。并将探讨其他CRTC家族成员的潜在监管贡献。在目标2中，将评估CRTC 3通过其对儿茶酚胺信号传导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物（NuRD）通过与CREB和CRTC 3的关联在沉默cAMP应答基因中的作用。这些研究将深入了解CREB：CRTC 3通路在引发脂肪早期变化中的重要性，这些变化导致肥胖症患者发生全身性胰岛素抵抗。

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.