TY - JOUR
T1 - Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1α transcriptional axis
AU - Ma, Xinran
AU - Xu, Lingyan
AU - Alberobello, Anna Teresa
AU - Gavrilova, Oksana
AU - Bagattin, Alessia
AU - Skarulis, Monica
AU - Liu, Jie
AU - Finkel, Toren
AU - Mueller, Elisabetta
PY - 2015/10/6
Y1 - 2015/10/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2015.08.005
DO - 10.1016/j.cmet.2015.08.005
M3 - Article
C2 - 26344102
AN - SCOPUS:84943455845
SN - 1550-4131
VL - 22
SP - 695
EP - 708
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -