Research ArticleMetabolism

TFEB drives PGC-1α expression in adipocytes to protect against diet-induced metabolic dysfunction

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Science Signaling  05 Nov 2019:
Vol. 12, Issue 606, eaau2281
DOI: 10.1126/scisignal.aau2281

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Browning fat with TFEB

TFEB is a transcription factor best known for its role in transcriptionally activating genes encoding autophagy factors. Evans et al. found that mice overexpressing TFEB in adipocytes were protected from the adverse metabolic consequences of a high-fat diet. TFEB promoted adipose tissue browning, a process in which white adipose tissue acquires the energy-burning properties of brown adipose tissue, through the transcriptional coactivator PGC-1α, rather than the induction of autophagy genes. These results suggest that increasing TFEB expression in adipocytes could be a therapeutic strategy to stave the metabolic dysfunction caused by a high-fat diet.


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.

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