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A multi-functional oral small molecule targeting energy and lipid metabolism as a treatment for diet-induced obesity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE302447 | GEO | 2026/07/06

REPOSITORIES: GEO

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A multi-functional oral small molecule targeting energy and lipid metabolism as a treatment for diet-induced obesity [Exp 5]

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Project description: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.

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