Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance

Svetlana Altshuler-Keylin, Kosaku Shinoda, Yutaka Hasegawa, Kenji Ikeda, Haemin Hong, Qianqian Kang, Yangyu Yang, Rushika M. Perera, Jayanta Debnath, Shingo Kajimura

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)402-419
Number of pages18
JournalCell metabolism
Volume24
Issue number3
DOIs
StatePublished - Sep 13 2016

Keywords

  • beige adipocytes
  • diabetes
  • mitochondria
  • mitophagy
  • obesity

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Altshuler-Keylin, S., Shinoda, K., Hasegawa, Y., Ikeda, K., Hong, H., Kang, Q., Yang, Y., Perera, R. M., Debnath, J., & Kajimura, S. (2016). Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell metabolism, 24(3), 402-419. https://doi.org/10.1016/j.cmet.2016.08.002