Atg6 in Protection Against Insulin Resistance

描述（由申请人提供）：骨骼肌胰岛素抵抗是2型糖尿病的前驱症状，与线粒体损伤相关，也可能是线粒体损伤的结果。自噬是一种分解代谢过程，可降解聚集体蛋白和受损细胞器（如线粒体），可能对维持代谢稳态至关重要。Atg6是一种启动自噬所必需的蛋白质，与Bcl-2家族蛋白相互作用并被Bcl-2家族蛋白抑制，Bcl-2家族蛋白将Atg6连接到线粒体膜上。我们最近利用多系统方法表明：1)Vps30 （Atg6的酵母同源物）的过表达保护出芽酵母细胞免受线粒体解偶联剂cccp诱导的生长停滞；2)饱和脂肪酸摄食和杂合Atg6基因缺失都会导致果蝇间接飞行肌中受损线粒体的积累；3)与高脂肪饮食的野生型鼠相比，Atg6+/-小鼠出现葡萄糖耐受不良。这些发现有力地支持了Atg6在应对线粒体损伤和维持代谢稳态中的保守功能，从酵母到哺乳动物。我的中心假设是通过Bcl-2释放Atg6诱导自噬在维持胰岛素敏感性和骨骼线粒体健康中起关键作用

DESCRIPTION (provided by applicant): Insulin resistance in skeletal muscle, a prodrome of type 2 diabetes mellitus, is associated with and a likely consequence of mitochondrial damage. Autophagy, a catabolic process that degrades aggregate proteins and damaged organelles, such as mitochondria, may be crucial in maintaining metabolic homeostasis. Atg6, a protein essential in initiating autophagy, interacts with and is inhibited by Bcl-2 family proteins that tether Atg6 to the mitochondrial membrane. We have recently utilized a multisystem approach to show: 1) overexpression of Vps30 (yeast homolog of Atg6) protects budding yeast cells against mitochondrial uncoupler CCCP-induced growth arrest; 2) both saturated fatty acid feeding and heterozygous Atg6 gene deletion lead to accumulation of damaged mitochondria in drosophila indirect flight muscles; and 3) Atg6+/- mice appear glucose intolerant compared to wild type littermates on high-fat diet. These findings strongly support conserved function of Atg6 in coping with mitochondrial damage and maintaining metabolic homeostasis ranging from yeast to mammals. My central hypothesis is that induction of autophagy through release of Atg6 from Bcl-2 plays a critical role in maintaining insulin sensitivity and mitochondrial health in skeletal muscle following high-fat diet in mice. To test this central hypothesis, I propose the following specific aims: Specific Aim 1. To ascertain whether Atg6 is sufficient and necessary to maintain a healthy mitochondrial population and prevent insulin resistance in skeletal muscle induced by high-fat diet in mice. Specific Aim 2. To determine if lipid overload-induced mitochondrial damage leads to release of Atg6 from mitochondrial Bcl-2 in skeletal muscle. Significance. These experiments will define the essential function and regulation of autophagy in maintaining a healthy mitochondrial population and therefore preserving skeletal muscle insulin sensitivity in response to mitochondrial damage; thereby, identifying potential new therapeutic targets to combat insulin resistance and diabetes. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a complex disease which originates with peripheral resistance to insulin, often the onset occurs at the skeletal muscle. This disease has been associated with the degeneration of mitochondria (the cell's powerplant), therefore targeting the removal of degenerated mitochondria by a process called autophagy, may ameliorate insulin resistance and type 2 diabetes. In these studies we will elucidate the role of mitochondrial stress-induced autophagy in the onset of insulin resistance.