High-Fat Diet Triggers Inflammation-Induced Cleavage of SIRT1 in Adipose Tissue To Promote Metabolic Dysfunction

SummaryAdipose 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 inflammation and obesity under normal feeding conditions, and to forestall the progression to metabolic dysfunction under dietary stress and aging. Genetic ablation of SIRT1 in 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 protein in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.

► SIRT1 loss from adipose tissue leads to obesity and metabolic dysfunction ► Adipose SIRT1 deletion and HFD induce similar changes in gene expression ► Obesity and inflammation result in reduced SIRT1 activity in adipose tissue ► The inflammation-induced caspase-1 cleaves and destabilizes SIRT1 protein