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Cell Metab. 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.

Author information

  • 1Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3Clinical Endocrine Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: elisabettam@niddk.nih.gov.

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.

PMID:
26344102
DOI:
10.1016/j.cmet.2015.08.005
[PubMed - indexed for MEDLINE]
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