TFEB drives PGC-1α expression in adipocytes to protect against diet-induced metabolic dysfunction
- 5 November 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 12 (606)
- https://doi.org/10.1126/scisignal.aau2281
Abstract
TFEB is a basic helix-loop-helix transcription factor that confers protection against metabolic diseases such as atherosclerosis by targeting a network of genes involved in autophagy-lysosomal biogenesis and lipid catabolism. In this study, we sought to characterize the role of TFEB in adipocyte and adipose tissue physiology and evaluate the therapeutic potential of adipocyte-specific TFEB overexpression in obesity. We demonstrated that mice with adipocyte-specific TFEB overexpression (Adipo-TFEB) were protected from diet-induced obesity, insulin resistance, and metabolic sequelae. Adipo-TFEB mice were lean primarily through increased metabolic rate, suggesting a role for adipose tissue browning and enhanced nonshivering thermogenesis in fat. Transcriptional characterization revealed that TFEB targeted genes involved in adipose tissue browning rather than those involved in autophagy. One such gene encoded PGC-1α, an established target of TFEB that promotes adipocyte browning. To dissect the role of PGC-1α in mediating the downstream effects of TFEB overexpression, we generated mice with adipocyte-specific PGC-1α deficiency and TFEB overexpression. Without PGC-1α, the ability of TFEB overexpression to brown adipose tissue and to elicit beneficial metabolic effects was blunted. Overall, these data implicate TFEB as a PGC-1α–dependent regulator of adipocyte browning and suggest its therapeutic potential in treating metabolic disease.Funding Information
- American Diabetes Association (ADA #1-18-IBS-029)
- National Heart, Lung, and Blood Institute (HL125838)
- National Heart, Lung, and Blood Institute (F31 HL132434)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK020579)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIH R01 DK115867)
- U.S. Department of Veterans Affairs (I01 BX003415)
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