Role of Adipose Autophagy in Metabolism

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.