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 language | English (US) |
|---|---|
| Pages (from-to) | 402-419 |
| Number of pages | 18 |
| Journal | Cell Metabolism |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 13 2016 |
| Externally published | Yes |
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Keywords
- beige adipocytes
- diabetes
- mitochondria
- mitophagy
- obesity
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. / Altshuler-Keylin, Svetlana; Shinoda, Kosaku; Hasegawa, Yutaka; Ikeda, Kenji; Hong, Haemin; Kang, Qianqian; Yang, Yangyu; Perera, Rushika M.; Debnath, Jayanta; Kajimura, Shingo.
In: Cell Metabolism, Vol. 24, No. 3, 13.09.2016, p. 402-419.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance
AU - Altshuler-Keylin, Svetlana
AU - Shinoda, Kosaku
AU - Hasegawa, Yutaka
AU - Ikeda, Kenji
AU - Hong, Haemin
AU - Kang, Qianqian
AU - Yang, Yangyu
AU - Perera, Rushika M.
AU - Debnath, Jayanta
AU - Kajimura, Shingo
PY - 2016/9/13
Y1 - 2016/9/13
N2 - 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.
AB - 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.
KW - beige adipocytes
KW - diabetes
KW - mitochondria
KW - mitophagy
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=84990866320&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990866320&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2016.08.002
DO - 10.1016/j.cmet.2016.08.002
M3 - Article
C2 - 27568548
AN - SCOPUS:84990866320
VL - 24
SP - 402
EP - 419
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 3
ER -