ARRA Supplement P&F Grant Award - Do-Hyung Kim, Ph.D.

Role of Adipose Autophagy in Insulin Resistance

Do-Hyung Kim, Ph.D.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota

Our research 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 nutrient-regulated 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. 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 the crucial molecular step 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 mAtg13 (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. Our recent studies led us to discover that mTOR regulates autophagy induction through phosphorylation of ULK1 and mAtg13. Given this knowledge on the fundamental mechanism underlying the regulation of autophagy induction, our proposed research will be more focused on understanding the physiological roles of adipose autophagy in insulin signaling and metabolism. We plan to test our central hypothesis by pursing the specific aim to determine the roles of ULK1 and mAtg13, the components essential for autophagy induction, in the regulation of adipocyte differentiation, fat metabolism, and insulin sensitivity. This project will be made possible through the close, synergistic collaboration between three investigators, Dr. Kim having expertise in the mTOR field, Dr. Arriaga having expertise in mitochondrial research, and Dr. Bernlohr having expertise in adipose biology. The three laboratories have joined forces to study adipose autophagy by determining the crucial molecular steps in the regulation of fat cell energy metabolism and the relationship of autophagy to obesity and insulin resistance.