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

描述（由申请人提供）：葡萄糖和脂质稳态通常是通过胰岛素敏感组织之间的激素和营养信号通路网络维持的。事实上，组织间通讯的中断通常与II型糖尿病有关，尽管触发这一过程的初始事件尚未被描述。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；缺乏肥胖CREB活性的小鼠在饮食或遗传肥胖的情况下仍然对胰岛素敏感。目前的建议解决了CREB共激活子CRTC3在介导CREB在脂肪中的代谢作用中的重要性。提出了三个目标；在Aim 1中，将对CRTC3基因破坏导致胰岛素敏感性和饮食性肥胖抵抗的机制进行表征。将确定营养和饮食状况在触发能量消耗、食物摄入和身体活动中crtc3依赖性变化中的作用。并将探讨其他CRTC家族成员在监管方面的潜在贡献。在Aim 2中，将评估CRTC3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Aim 3中，核小体重塑和去乙酰化酶复合体（NuRD）通过与CREB和CRTC3的关联，在沉默cAMP应答基因中的作用将被表征。这些研究将深入了解CREB:CRTC3通路在触发脂肪早期变化中的重要性，从而导致肥胖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. PUBLIC HEALTH RELEVANCE: Obesity is a major risk factor in the development of type II diabetes, a disease that affects more than 20 million individuals in the United States. The current application addresses how a fasting switch called CRTC3 promotes insulin resistance in the context of diet induced obesity. The studies will provide insight into molecular mechanisms by which increases in adiposity lead to systemic changes in insulin sensitivity.