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

Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance.

Author information

1
UCSF Diabetes Center, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
UCSF Diabetes Center, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: skajimura@diabetes.ucsf.edu.

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.

KEYWORDS:

beige adipocytes; diabetes; mitochondria; mitophagy; obesity

PMID:
27568548
PMCID:
PMC5023491
DOI:
10.1016/j.cmet.2016.08.002
[Indexed for MEDLINE]
Free PMC Article

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