Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Metab. 2015 Oct 6;22(4):695-708. doi: 10.1016/j.cmet.2015.08.005. Epub 2015 Sep 3.
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.
改变能量摄入和支出之间的平衡是治疗肥胖症和代谢综合征的一种潜在策略。尽管在确定多种分子靶点方面取得了多年的进展，但基于生物学的治疗方法仍然有限。在这里，我们证明热休克因子 1（HSF1）通过激活脂肪组织和肌肉中的 PGC1α 依赖性代谢程序来调节能量消耗。HSF1 水平的遗传调节改变了白色脂肪重塑和产热，并且通过塞拉托林（celastrol）对 HSF1 的药理学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肪饮食方案中预防肥胖、胰岛素抵抗和肝脂肪变性有关。塞拉托林引起的有益代谢变化在 HSF1 敲除小鼠中被消除。总的来说，我们的研究结果确定了温度传感器 HSF1 作为能量代谢的调节剂，并证明通过塞拉托林增强 HSF1 可能是治疗肥胖症及其多种代谢后果的一种治疗策略。
