Cystathionine γ lyase-hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes.

Abstract Adipocytes express the cystathionine γ lyase (CSE)–hydrogen sulfide (H 2 S) system. CSE–H 2 S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE–H 2 S induces these paradoxical effects. First, we confirmed that an H 2 S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H 2 S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H 2 S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H 2 S induced peroxisome proliferator activated receptor γ (PPARγ) protein and mRNA expression. Of note, H 2 S directly sulfhydrated PPARγ protein. Sulfhydrated PPARγ increased its nuclear accumulation, DNA binding activity and adipogenesis gene expression, thereby increasing glucose uptake and lipid storage, which were blocked by the desulfhydration reagent DTT. H 2 S induced PPARγ sulfhydration, which was blocked by mutation of the C139 site of PPARγ. In mice fed a high-fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H 2 S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H 2 S treatment increased PPARγ sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE–H 2 S increased PPARγ activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE–H 2 S-mediated PPARγ activation might be a new therapeutic target for diabetes associated with obesity.