@article{d1df04e85c874ceca31cdda9b05cf168,
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.",
keywords = "beige adipocytes, diabetes, mitochondria, mitophagy, obesity",
author = "Svetlana Altshuler-Keylin and Kosaku Shinoda and Yutaka Hasegawa and Kenji Ikeda and Haemin Hong and Qianqian Kang and Yangyu Yang and Perera, {Rushika M.} and Jayanta Debnath and Shingo Kajimura",
note = "Funding Information: We are grateful to Dr. Luke Cassereau and Dr. Valerie Weaver at University of California, San Francisco for their help in developing the single-cell monitoring system, Anthony Jose from the FACS Core for his help in isolating mature adipocytes, Dr. Noboru Mizushima at the University of Tokyo for providing GFP-LC3 mice, Dr. Evan Rosen at Beth Israel Deaconess Medical Center and Harvard Medical School for providing Ucp1 Cre/+ mice, Dr. Christophe Paillart for his help in the CLAMS studies, and Larry Ackerman for his help with EM. We acknowledge support from the NIH ( DK97441 and DK108822 ), the Diabetes and Endocrine-Related Disease Center (DERC) ( DK63720 ), the Pew Charitable Trust , and the Japan Science and Technology Agency (to S.K.), NIH CA126792 (to J.D.), the American Cancer Society , and the Pancreatic Cancer Action Network - AACR Career Development award (to R.M.P.). S.A.-K. is supported by American Heart Association (AHA) grant 15PRE23050029 and the California Institute for Regenerative Medicine (CIRM) grant TG2-01153 . K.S. is supported by the Larry L. Hillblom Foundation (LLHF) grant 2014-D-025-FEL . Y.H. and K.I. are supported by the Manpei Suzuki Diabetes Foundation . Q.K. is supported by the China Scholarship Council (CSC) grant 201506350063 . ",
year = "2016",
month = sep,
day = "13",
doi = "10.1016/j.cmet.2016.08.002",
language = "English (US)",
volume = "24",
pages = "402--419",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}