Caspase-1在白色脂肪米色化中的作用和机制研究

米色脂肪可通过产热增加能量消耗，抵抗高脂饮食诱导的肥胖并改善代谢。Caspase-1作为炎症小体组分剪切前体产生活性IL-1β和IL-18，参与肥胖相关炎症和胰岛素抵抗，但它在白色脂肪米色化中的作用尚不清楚。我们发现Caspase-1在冷暴露的白色脂肪中下调，基因敲除小鼠的米色化能力增强。根据本课题组前期结果提出假设：冷暴露激活的cAMP信号使Caspase-1下调，糖酵解通路相关酶作为其底物裂解减少，进而增强糖酵解促进白色脂肪米色化。本课题拟从人群、动物水平研究Caspase-1与肥胖和米色化的相关性；利用基因敲除小鼠和过表达腺病毒等在动物和细胞水平探究Caspase-1在米色化中的作用；用代谢组学，细胞代谢分析，干扰下游靶基因等方法探索其机制。通过本研究可深刻理解Caspase-1在白色脂肪米色化中的作用及分子机制，为治疗肥胖及相关疾病提供分子靶点。

The beiging of white adipose tissue can enhance energy expenditure, resist high-fat-diet-induced obesity and improve insulin sensitivity. Caspase-1, a key member of the inflammasome, acts as a cysteine protease to cleave IL-1β and IL-18 precursors into active form and take a part in obesity induced inflammation and insulin resistance. However, the role of Caspase-1 in white adipose tissue beiging remains unclear. We found that Caspase-1 was down-regulated in subcutaneous fat under cold exposure, and the beiging was enhanced in caspase-1-/- mice. Based on published reports and our previous study, we hypothesize that cold exposure induced cAMP signal activation can down-regulate Caspase-1 and reduce the cleavage of glycolysis pathway related enzymes which governed by Caspase-1, result in enhancing glycolysis and promoting white adipose tissue beiging. To confirm the hypothesis, we try to find the correlation among Caspase-1, obesity and beige adipocytes from the human and mice subjects. Using Caspase-1 knockout mice, Caspase-1 adipocyte-specific knockout mice and Caspase-1 over-expressed mice, we will explore the role of Caspase-1 in the beiging process at the animal and cell levels. We will employ metabonomics, seahorse cell metabolism analysis, and interference downstream target genes of Caspase-1 to explore the molecular mechanism of Caspase-1 in white adipocyte beiging. This study can provide deeply understanding on the molecular mechanism of Caspase-1 on beiging of adipose tissue, and provide potential targets for the prevention and treatment of obesity.