Piceatannol Inhibits Lipolysis in Adipocytes by promoting autophagy‐lysosome‐induced degradation of Lipolytic Proteins

Obesity is closely linked to the development of insulin resistance. This is largely through overly activated lipolysis in adipose tissue for providing excess fatty acids to peripheral tissues for developing hyperglycemia. Adipose triglyceride lipase (ATGL)/desnutrin, catalyzes the initial and rate‐limiting step of triglyceride hydrolysis for the release of free fatty acids to circulation. Thus, inhibiting lipolysis by lowering ATGL activity and/or expression has been proposed to be a therapeutic approach to improve glucose tolerance and insulin sensitivity in obesity. The objective of this study was to determine the role of piceatannol, a resveratrol analogue found in various fruits and red wine, in adipose lipolysis. Unlike resveratrol, acute treatment of piceatannol inhibited the release of glycerol and fatty acids from 3T3‐L1 adipocytes and isolated mouse adipose tissue both in basal and stimulated conditions. Piceatannol‐inhibited lipolysis was resulted from marked decrease in ATGL and its cofactor CGI‐58 protein levels with little effect on the mRNA levels. Consistently, intraperitoneal administration of piceatannol to obese mice lowered plasma levels of lipolysis markers and insulin, with reduced ATGL level in adipose tissue. Mechanistically, we elucidated that the anti‐lipolytic effect of piceatannol was through piceatannol‐induced lysosomal degradation of ATGL and CGI‐58 via activation of autophagy in adipocytes. Overall, our results identified piceatannol as a natural anti‐lipolytic small molecule that could uncouple obesity from its related metabolic diseases. Moreover, our study provides new insights into autophagy‐lysosome‐dependent regulation of adipose lipolysis.