Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis.
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.
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Xinran
X
Ma
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Lingyan
L
Xu
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Anna Teresa
AT
Alberobello
Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Oksana
O
Gavrilova
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Alessia
A
Bagattin
Clinical Endocrine Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Monica
M
Skarulis
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jie
J
Liu
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Toren
T
Finkel
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.
Elisabetta
E
Mueller
D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053978:Pentacyclic Triterpenes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D022722:Thermogenesis / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000032:analysis / Q000097:blood; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D053978:Pentacyclic Triterpenes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; D014315:Triterpenes; C050414:celastrol