High Fat Diet Triggers SIRT1 Cleavage in Adipose Tissue Providing a Link between Dietary Stress and Metabolic Dysfunction

Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction. Four replicates from four different biological conditions: 1) SIRT1 wild-type fed low fat diet, 2) SIRT1 wild-type fed high fat diet, 3) SIRT1 knock-out fed low fat diet, 4) SIRT1 knock-out fed high fat diet脂肪组织(adipose tissue)在储存过剩营养物质、防止异位脂质在其他器官异常堆积方面发挥关键作用。肥胖可导致脂肪细胞内脂质过度储存，进而产生应激信号并扰乱代谢功能。SIRT1是多种代谢组织中感知营养可利用性的重要调控传感器。本研究表明，SIRT1在脂肪组织中发挥功能，可在正常饲喂条件下抵御炎症与肥胖的发生，并在膳食应激条件下阻止代谢功能异常的进展。从脂肪组织中敲除SIRT1所引发的基因表达变化，与野生型小鼠经高脂饮食诱导后的基因表达变化高度重合，这提示膳食应激信号可抑制SIRT1的活性。进一步实验证实，高脂饮食会通过炎症激活的半胱天冬酶-1(caspase-1)介导脂肪组织中SIRT1的剪切，从而建立起膳食应激与代谢功能异常易感性之间的联系。本数据集包含4种不同生物学条件下的4次生物学重复：1) 低脂饮食饲喂的SIRT1野生型小鼠样本；2) 高脂饮食饲喂的SIRT1野生型小鼠样本；3) 低脂饮食饲喂的SIRT1敲除型小鼠样本；4) 高脂饮食饲喂的SIRT1敲除型小鼠样本