Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance

Beige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote beige adipocyte differentiation, the molecular basis of beige adipocyte maintenance remains unknown. Here, we demonstrate that beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli and directly acquire white-like characteristics bypassing an intermediate precursor stage. The beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by uncoupled protein 1 (UCP1+)-adipocyte-specific deletion of Atg5 or Atg12 prevents beige adipocyte loss after withdrawing external stimuli, maintaining high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls beige adipocyte maintenance, thereby providing new opportunities to counteract obesity. [Display omitted] •Beige adipocytes directly acquire a “white-like” state after withdrawing stimuli•Autophagy is activated during the beige-to-white fat transition•Genetic and pharmacological inhibition of autophagy retains beige adipocytes•Prolonged maintenance of beige fat ameliorates obesity and glucose intolerance When exposed to thermogenic stimuli, beige adipocytes transiently express UCP1 but lose that expression upon stimuli withdrawal. Altshuler-Keylin et al. investigate beige adipocyte maintenance and show that autophagy-mediated mitochondrial clearance is needed for beige-to-white adipocyte reversal. Inhibition of autophagy maintains functional beige adipocytes even after stimuli withdrawal.