Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance

Cell Metab. 2016 Sep 13;24(3):402-419. doi: 10.1016/j.cmet.2016.08.002. Epub 2016 Aug 25.


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.

Keywords: beige adipocytes; diabetes; mitochondria; mitophagy; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Beige / cytology*
  • Adipocytes, Beige / drug effects
  • Adipocytes, Beige / metabolism*
  • Adipocytes, White / cytology
  • Adipocytes, White / drug effects
  • Adrenergic beta-3 Receptor Agonists / pharmacology
  • Animals
  • Autophagy* / drug effects
  • Autophagy-Related Proteins / metabolism
  • Cell Shape / drug effects
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diet, High-Fat
  • Gene Deletion
  • Insulin Resistance
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Obesity / metabolism
  • Obesity / pathology
  • Organelle Biogenesis
  • Phenotype
  • Signal Transduction / drug effects


  • Adrenergic beta-3 Receptor Agonists
  • Autophagy-Related Proteins
  • Microphthalmia-Associated Transcription Factor
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases