Caspase‐6 Controls Lipid and Energy Metabolism in Diet‐Induced Obesity

ABSTRACT Caspases are cysteine proteases that regulate programmed cell death. While caspase‐6, an executioner caspase, is known for its role in neurodegeneration and cell death, its broader physiological functions remain poorly understood. Our previous study revealed that caspase‐6 drives liver injury and fibrosis in metabolic dysfunction‐associate steatohepatitis. Here, we report that caspase‐6 deficiency protects against high fat diet‐induced obesity. Both global and adipocyte‐specific caspase‐6 knockout mice exhibit increased energy expenditure, reduced adiposity and inflammation, and improved glucose metabolism. Mechanistically, caspase‐6 directly cleaves peroxisome proliferator‐activated receptor gamma (PPARγ) and its cofactor specificity protein 1 (SP1), thereby suppressing adipose triglyceride lipase (ATGL) expression. Caspase‐6 deficiency restores ATGL, enhancing lipolysis and elevating fatty acyl esters of hydroxy fatty acids (FAHFAs), which alleviate inflammation and enhance insulin sensitivity. These findings uncover a novel Casp6‐PPARγ/SP1‐ATGL axis in adipose tissue and establish caspase‐6 as a potential therapeutic target for obesity and insulin resistance.