title: Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance.
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.
authors: 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.
authors: Svetlana
authors: S
authors: Altshuler-Keylin
authors: 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.
authors: Kosaku
authors: K
authors: Shinoda
authors: 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.
authors: Yutaka
authors: Y
authors: Hasegawa
authors: 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.
authors: Kenji
authors: K
authors: Ikeda
authors: 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.
authors: Haemin
authors: H
authors: Hong
authors: 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.
authors: Qianqian
authors: Q
authors: Kang
authors: 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.
authors: Yangyu
authors: Y
authors: Yang
authors: 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.
authors: Rushika M
authors: RM
authors: Perera
authors: 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.
authors: Jayanta
authors: J
authors: Debnath
authors: 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.
authors: Shingo
authors: S
authors: Kajimura
mesh_terms: D000069797:Adipocytes, Beige / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059305:Diet, High-Fat; D017353:Gene Deletion; D007333:Insulin Resistance; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000071183:Autophagy-Related Proteins; D051739:Microphthalmia-Associated Transcription Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: beige adipocytes; diabetes; mitochondria; mitophagy; obesity