Distinct functions of autophagy kinases ULK1 and ULK2 in adipogenesis and adipocyte metabolism

Abstract

Autophagy, the catabolic process through which intracellular constituents are degraded in the lysosome under nutrient starvation or stress, has gained growing attention in the field of diabetes and obesity (Goldman S 2010; Ost A 2010; Beau I 2011; Kovsan J 2011). Despite the fundamental cellular function of autophagy in maintaining cellular energy homeostasis and survival under nutrient– or energy– deprived conditions and stress, the role of adipose autophagy in metabolism and metabolic diseases remains largely unknown. The goal of my study has been to better understand the function of autophagy in adipogenesis and in the regulation of adipocyte metabolism. My study has been focused on defining the role of ULK1 (Unc–51 like kinase 1, mammalian homolog of Atg1, hATG1) and its homologue ULK2 in the regulation of adipogenesis, metabolism and mitochondrial functions in adipocytes. ULK1 and ULK2 are key regulators of autophagy induction in mammalian cells (Kundu M 2009; Chang YY 2009; Ganley IG 2009; Hosokawa N 2009; Jung CH 2009). Knockdown of ULK1 or ULK2 inhibited autophagy in 3T3–L1 adipocytes, suggesting that they play important roles in autophagy in adipocytes. The knockdown experiment also revealed that ULK1 and ULK2 share key functions in lipolysis, mitochondrial respiration and protection of cells against oxidative stress. Despite these shared functions, their knockdown had different or even opposing effects on several metabolic parameters. Knockdown of ULK1 raised PPAR–γ level, facilitated differentiation of 3T3–L1 cells, increased the levels of GLUT4, insulin receptorβ(IRβ) and insulin receptor substrate–1 (IRS–1), and insulin–stimulated glucose uptake, and reduced fatty acid oxidation. By contrast, knockdown of ULK2 had opposite or no significant effects on these parameters. Through knocking down both ULK1 and ULK2, we found that ULK2 has a dominant effect over ULK1 in the regulation of adipogenesis. These results demonstrate that ULK1 and ULK2 have distinct functions in the regulation of adipogenesis and adipocyte metabolism, and that ULK2–dependent autophagy appears to be important for adipogenesis.