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

Xinran Ma; Lingyan Xu; Anna Teresa Alberobello; Oksana Gavrilova; Alessia Bagattin; Monica Skarulis; Jie Liu; Toren Finkel; Elisabetta Mueller

doi:10.1016/j.cmet.2015.08.005

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.

Authors

Xinran Ma¹, Lingyan Xu¹, Anna Teresa Alberobello¹, Oksana Gavrilova², Alessia Bagattin¹, Monica Skarulis³, Jie Liu⁴, Toren Finkel⁴, Elisabetta Mueller⁵

Affiliations

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

PMID: 26344102
DOI: 10.1016/j.cmet.2015.08.005

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*
Pentacyclic Triterpenes
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
Pentacyclic Triterpenes
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Transcription Factors
Triglycerides
Triterpenes
celastrol

Grants and funding

Intramural NIH HHS/United States