FoxO1 regulates beige adipogenesis and adiposity via autophagy

Abstract

The transcription factor forkhead box O1 (FoxO1) plays an important role in autophagy and metabolic homeostasis. Previous studies from our lab and others have shown that FoxO1 is required for autophagy and white adipocyte differentiation. However, it remains largely unknown whether and how FoxO1 mediates beige adipogenesis, a cellular event that promotes energy expenditure through mitochondrial uncoupling and thermogenesis. To address this question, we modulated FoxO1 activity in primary white adipocytes in vitro with FoxO1 antagonist (AS1842856). AS1842856 increased mitochondrial uncoupling protein UCP1, concomitant with upregulation of mitochondrial respiration chain proteins. These changes were associated with suppressed autophagy as evaluated by LC3 and p62. Interestingly, treatment of white adipocytes with classic autophagy inhibitor bafilomycin A1 also increased UCP1 and mitochondrial respiration chain protein, suggesting that FoxO1 may regulate beiging of white adipocytes via autophagy. Indeed, knockout (KO) of FoxO1 in mouse adipose tissue dampens autophagy and promotes beiging phenotype (i.e., upregulation of UCP1 and other mitochondrial contents). In line with beige adipogenesis priming energy expenditure through thermogenesis, the FoxO1‐KO mice showed significantly higher body temperature and lower adiposity. Together, our data reveals a role for FoxO1 to mediate beiging of white adipocytes by regulating autophagy, and suggests that targeting adipocyte FoxO1 may lead to new strategies to treat or prevent obesity.Support or Funding InformationUSDA National Institute of Food and Agriculture Hatch Project 1007334 (Z.C.) and American Heart Association Grant 18TPA34230082 (Z.C.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.