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

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

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism
  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diet, High-Fat
  • Energy Metabolism / drug effects*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Heat Shock Transcription Factors
  • Humans
  • Liver / metabolism
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology
  • Metabolic Syndrome / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism
  • Obesity / pathology
  • Obesity / prevention & control*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic
  • Thermogenesis / drug effects
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Triglycerides / analysis
  • Triglycerides / blood
  • Triterpenes / pharmacology*
  • Triterpenes / therapeutic use

Substances

  • DNA-Binding Proteins
  • Heat Shock Transcription Factors
  • Hsf1 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • Triglycerides
  • Triterpenes
  • celastrol