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

Adipocytes express the cystathionine gamma lyase (CSE)-hydrogen sulfide (H2S) system. CSE-H2S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE-H2S induces these paradoxical effects. First, we confirmed that an H2S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H2S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H2S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H2S induced peroxisome proliferator activated receptor gamma (PPAR gamma) protein and mRNA expression. Of note, H2S directly sulfhydrated PPAR gamma protein. Sulfhydrated PPAR gamma 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. H2S induced PPAR gamma sulfhydration, which was blocked by mutation of the C139 site of PPAR gamma. In mice fed a high-fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H2S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H2S treatment increased PPAR gamma sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE-H2S increased PPAR gamma activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE-H2S-mediated PPAR gamma activation might be a new therapeutic target for diabetes associated with obesity. (C) 2016 Elsevier B.V. All rights reserved.Major State Basic Research Development Program of the People's Republic of China [2012CB517806]; National Natural Science Foundation of China [81170235, 81470552, 91339106, 91439119]SCI(E)PubMedARTICLEbingeng@hsc.pku.edu.cn5419-429186