Autophagy regulates adipose mass and differentiation in mice

TLDR

The relative proportions of white versus brown adipose tissue critically influence lipid storage and whole‑body energy balance, yet the mechanisms governing their formation, expansion, and interconversion remain unclear. This study examined whether autophagy regulates adipocyte differentiation by genetically inhibiting the macroautophagy gene Atg7. Loss of Atg7 (or other autophagy components) impaired lipid accumulation and adipogenic factor expression in vitro, and adipocyte‑specific Atg7 knockout mice were lean, had reduced white fat, increased brown‑like features, higher fatty‑acid oxidation, and improved insulin sensitivity, demonstrating that autophagy controls body lipid accumulation by modulating adipocyte differentiation and the white‑brown fat balance.

Abstract

The relative balance between the quantity of white and brown adipose tissue can profoundly affect lipid storage and whole-body energy homeostasis. However, the mechanisms regulating the formation, expansion, and interconversion of these 2 distinct types of fat remain unknown. Recently, the lysosomal degradative pathway of macroautophagy has been identified as a regulator of cellular differentiation, suggesting that autophagy may modulate this process in adipocytes. The function of autophagy in adipose differentiation was therefore examined in the current study by genetic inhibition of the critical macroautophagy gene autophagy-related 7 (Atg7). Knockdown of Atg7 in 3T3-L1 preadipocytes inhibited lipid accumulation and decreased protein levels of adipocyte differentiation factors. Knockdown of Atg5 or pharmacological inhibition of autophagy or lysosome function also had similar effects. An adipocyte-specific mouse knockout of Atg7 generated lean mice with decreased white adipose mass and enhanced insulin sensitivity. White adipose tissue in knockout mice had increased features of brown adipocytes, which, along with an increase in normal brown adipose tissue, led to an elevated rate of fatty acid, β-oxidation, and a lean body mass. Autophagy therefore functions to regulate body lipid accumulation by controlling adipocyte differentiation and determining the balance between white and brown fat.