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. 2015 Oct 6;22(4):695-708.
doi: 10.1016/j.cmet.2015.08.005. Epub 2015 Sep 3.

Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis

Xinran Ma  1 , Lingyan Xu  1 , Anna Teresa Alberobello  1 , Oksana Gavrilova  2 , Alessia Bagattin  1 , Monica Skarulis  3 , Jie Liu  4 , Toren Finkel  4 , Elisabetta Mueller  5
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Free article

Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis

Xinran Ma et al. Cell Metab. .
Free article

Abstract

Altering the balance between energy intake and expenditure is a potential strategy for treating obesity and metabolic syndrome. Nonetheless, despite years of progress in identifying diverse molecular targets, biological-based therapies are limited. Here we demonstrate that heat shock factor 1 (HSF1) regulates energy expenditure through activation of a PGC1α-dependent metabolic program in adipose tissues and muscle. Genetic modulation of HSF1 levels altered white fat remodeling and thermogenesis, and pharmacological activation of HSF1 via celastrol was associated with enhanced energy expenditure, increased mitochondrial function in fat and muscle and protection against obesity, insulin resistance, and hepatic steatosis during high-fat diet regimens. The beneficial metabolic changes elicited by celastrol were abrogated in HSF1 knockout mice. Overall, our findings identify the temperature sensor HSF1 as a regulator of energy metabolism and demonstrate that augmenting HSF1 via celastrol represents a possible therapeutic strategy to treat obesity and its myriad metabolic consequences.

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