Journal
CELL METABOLISM
Volume 24, Issue 3, Pages 402-419Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.08.002
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Funding
- NIH [DK97441, DK108822, CA126792]
- Diabetes and Endocrine-Related Disease Center (DERC) [DK63720]
- Pew Charitable Trust
- Japan Science and Technology Agency
- American Cancer Society
- Pancreatic Cancer Action Network-AACR
- American Heart Association (AHA) [15PRE23050029]
- California Institute for Regenerative Medicine (CIRM) [TG2-01153]
- Larry L. Hillblom Foundation (LLHF) [2014-D-025-FEL]
- Manpei Suzuki Diabetes Foundation
- China Scholarship Council (CSC) [201506350063]
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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.
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