Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury.

Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy-deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver remains unclear. To determine the role of adipose autophagy and mTOR in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (A-Atg5 KO), A- mTOR (mechanistic target of rapamycin) KO, A-Raptor KO, and A-TSC1 (tuberous sclerosis complex 1) KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type (WT) mice were challenged with chronic-plus-binge (Gao-binge) alcohol mouse model. Gao-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in WT mice. A-Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither A-mTOR nor A-TSC1 KO mice exhibited similar detrimental effects. A-Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 (FGF21) and adiponectin, which were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.