Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis
Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis
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DOI：
10.1016/j.cmet.2015.08.005
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发表时间：
2015-10-06
期刊：
影响因子：
29
通讯作者：
Mueller, Elisabetta
中科院分区：
文献类型：
--
作者：
Ma, Xinran;Xu, Lingyan;Mueller, Elisabetta
改变能量摄入和消耗之间的平衡是治疗肥胖和代谢综合征的一种潜在策略。然而，尽管在确定多种分子靶点方面取得了多年进展，但基于生物学的疗法仍然有限。在此我们证明，热休克因子1（HSF1）通过激活脂肪组织和肌肉中一种依赖于PGC1α的代谢程序来调节能量消耗。对HSF1水平的基因调控改变了白色脂肪的重塑和产热，通过雷公藤红素对HSF1进行药理激活与能量消耗增加、脂肪和肌肉中线粒体功能增强以及在高脂饮食方案期间预防肥胖、胰岛素抵抗和肝脂肪变性相关。雷公藤红素引发的有益代谢变化在HSF1基因敲除小鼠中消失。总体而言，我们的研究结果确定温度传感器HSF1是能量代谢的调节因子，并证明通过雷公藤红素增强HSF1代表了一种治疗肥胖及其众多代谢后果的可能治疗策略。
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 PGC1 alpha-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.