Role of Adipose Autophagy in Metabolism

我们的长期目标是增加与代谢有关的自噬机制的知识 糖尿病、肥胖症和胰岛素抵抗等疾病。自噬是一种进化保守的细胞 真核细胞在以下条件下消化大分子、细胞器或有缺陷的细胞成分的过程 饥饿或压力，而且它与各种人类疾病和 生理学，包括癌症、衰老、神经退化和微生物感染。共同的主题正在浮现 在各种研究中，自噬是在细胞中诱导的对线粒体功能障碍或 内质网(ER)应激作为体内平衡控制的一种机制。尽管传播范围如此之广 对自噬及其与代谢性疾病的联系，自噬之间的分子联系， 肥胖症和2型糖尿病尚未被广泛研究，自噬在脂肪代谢中的作用(S) 根本没有被探索过。我们提出的研究意在定义自噬的关键分子步骤。 诱导和自噬在调节脂肪能量代谢和胰岛素抵抗中的作用。这个 中心假说是mTOR调节的蛋白质复合体，它由ULK1(Unc51-like Protein 1)和 ATG13(酵母自噬基因13的哺乳动物同源基因)，在调节酵母自噬基因的功能中起着关键作用。 诱导脂肪组织中的自噬、胰岛素抵抗和能量代谢。关键的一步 自噬诱导包括抑制哺乳动物的雷帕霉素靶标(MTOR)，它是细胞的主控制器 生长和一种营养调节的蛋白激酶。MTOR调节自噬的机制 归纳仍然是难以捉摸的。目标1将通过确定ATG13和ATG13的作用来解决这个问题 MTOR介导的ATG13和ULK1在调节ULK1激酶活性中的磷酸化。给定 从目标1获得的机械知识，目标2中的研究将定向于定义如何 脂肪细胞和组织对营养或压力的反应以及ATG13和ULK1是如何调节自噬的 都参与了这项规定。目标#3将集中于了解脂肪自噬在 通过测定脂肪细胞中几个代谢参数调节代谢和胰岛素敏感性 以及自噬受到干扰的组织。这个项目将通过密切的、协同的 两名研究人员之间的合作，Kim博士拥有mTOR领域的专业知识，Bernlohr博士拥有 脂肪生物学方面的专业知识。这两个实验室已经联合起来，通过确定 脂肪细胞能量代谢调节中的关键分子步骤以及自噬与 肥胖和胰岛素抵抗。

Our long-term goal is to increase knowledge on autophagy-mediated mechanisms pertaining to metabolic diseases such as diabetes, obesity, and insulin resistance. Autophagy is an evolutionarily-conserved cellular process through which eukaryotic cells digest macromolecules, organelles or faulty cellular components under starvation or stress, and it has a significant growing number of links to a variety of human disease and physiology including cancer, aging, neurodegeneration, and microbial infection. The common theme emerging in a variety of studies on autophagy is induction in cells in response to mitochondrial dysfunction or endoplasmic reticulum (ER) stress as a mechanism for homeostatic control. Despite such wide spread appreciation for autophagy and its link to metabolic diseases, the molecular linkage between autophagy, obesity and type 2 diabetes has not been widely examined and the role(s) of autophagy in adipose metabolism has not been explored at all. Our proposed study is intended to define crucial molecular steps of autophagy induction and the autophagy roles in the regulation of adipose energy metabolism and insulin resistance. The central hypothesis is that mTOR-regulated protein complex, which consists of ULK1 (Unc51-like protein 1) and Atg13 (mammalian homolog of yeast AuToPhagy gene 13), plays a crucial role in the regulation of the induction of autophagy, insulin resistance, and energy metabolism in adipose tissue. A crucial step for autophagy induction involves inhibition of mammalian target of rapamycin (mTOR), a master controller of cell growth and a nutrient-regulated protein kinase. The mechanism through which mTOR regulates autophagy induction has remained elusive. Aim #1 will address this question by determining the roles of Atg13 and mTOR-mediated phosphorylation of Atg13 and ULK1 in the regulation of ULK1 kinase activity. Given the mechanical knowledge obtained from aim #1, the studies in Aim #2 will be oriented toward defining how autophagy is regulated in adipose cells and tissue in response to nutrients or stress and how Atg13 and ULK1 are involved in the regulation. Aim #3 will be focused to understand the roles of adipose autophagy in the regulation of metabolism and insulin sensitivity by determining several metabolic parameters in adipose cells and tissue where autophagy is disturbed. This project will be made possible through the close, synergistic collaboration between two investigators, Dr. Kim having expertise in the mTOR field and Dr. Bernlohr having expertise in adipose biology. Both laboratories have joined forces to study adipose autophagy by determining crucial molecular steps in the regulation of fat cell energy metabolism and the relationship of autophagy to obesity and insulin resistance.