Estradiol signaling interacts with Sirt1 in the regulation of autophagy and adipogenesis

Adiposity is regulated by estradiol signaling and the nutrient sensor Sirt1. It has been recognized that autophagy plays a key role in adipogenesis and metabolism. However, it remains largely unknown whether and how estradiol signaling interacts with Sirt1 in the regulation of autophagy. Here we showed that activation and overexpression of Sirt1 suppressed autophagy in 3T3L1 cells, which was associated with suppressed adipocyte differentiation. Treatment of preadipocytes with estradiol induced Sirt1 and dampened autophagy, thereby suppressing adipogenesis. Consistently, knockdown of Sirt1 induced autophagy and adipocyte differentiation, which was recapitulated by estrogen receptor inhibition or knockout. In addition, knockdown of Sirt1 abolished the effects of estradiol on autophagy and adipogenesis. The modulation of autophagy and adipogenesis by estradiol and Sirt1 was ascribed at least in part to mTOR‐ULK1 cascade. Protein analysis did not show significant changes in the acetylation levels of autophagy regulators (e.g., Atg5, Atg7, or LC3) during Sirt1 modulation. Taken together, our data reveals an estradiol‐Sirt1‐autophagy axis that regulates adipogenesis. Future study will be of interest and significance to determine the potential role of the estradiol‐Sirt1‐autophagy axis in sex‐dependent fat distribution. Support or Funding Information American Heart Association Grant 18TPA34230082 (Z.C.) and USDA National Institute of Food and Agriculture Hatch Project 1020373 (Z.C.).