Autophagy Ablation in Adipocytes Induces Insulin Resistance and Reveals Roles for Lipid Peroxide and Nrf2 Signaling in Adipose-Liver Crosstalk

Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues. [Display omitted] •Post-developmental deletion of autophagy in adipocytes causes insulin resistance•Mitochondrial dysfunction develops in autophagy-deficient adipocytes•Enhanced Nrf2 and Keap1 signaling in autophagy-deficient adipocytes•Crosstalk between fat and liver mediated by lipid peroxide-induced Nrf2 signaling Cai et al. describe how lack of autophagy in mature adipocytes causes insulin resistance with no change in body weight. Adipocytes lacking Atg3 or Atg16L1 accumulate dysfunctional mitochondria and have increased lipid peroxidation and Nrf2 and keap1 activation. This study reveals a role for lipid peroxides and Nrf2 signaling in an adipose-liver crosstalk.