GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE311nnn/GSE311559/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE311559GEOGSEfalseCaspase-6 Controls Lipid and Energy Metabolism in Diet-Induced ObesityCaspases 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.2026/04/22GSE311559GSM9327030GSM9327021GSM9327032GSM9327031GSM9327020GSM9327019GSM9327027GSM9327026GSM9327029GSM9327028GSM9327023GSM9327034GSM9327033GSM9327022GSM9327036GSM9327025GSM9327035GSM932702430172311559Mus musculus[41969066]