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

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.

RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs

“…Homozygous Pspc1-floxed mice carrying the conditional-ready knockout allele were used for adenovirus-Cre injection studies. For the adenovirus delivery to fat pads, 2 × 10 9 PFU of adenovirus was percutaneously injected into the inguinal fat depot at 8 weeks of age (71). In each mouse, Ad-Cre was injected on one side, and Ad-GFP was injected on the contralateral side.…”

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

“…Analysis of serum chemistry including cholesterol, triglyceride, and creatine kinase levels were performed by the Department of Laboratory Medicine at the NIH Clinical Center. Glucose tolerance and insulin tolerance tests and liver triglyceride levels were determined as previously described (49,50).…”

Heat stress induces mitochondrial adaptations in skeletal muscle

“…The recent computational study showed that HSE was found in the promoter region of PGC-1α 27) , suggesting transcription of the PGC-1α gene can also be regulated by HSF1. Actually, another recent report has shown that HSF1 positively regulates PGC-1α transcription in adipose tissues and skeletal muscles 28) . Interestingly, although HSR is thought to be the basic preservative and essential process of cell protection, HSF1-dependent PGC-1α transcription depends on tissue type (e.g.…”