title: 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 (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 γ (PPARγ) protein and mRNA expression. Of note, H2S 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. H2S 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 H2S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H2S treatment increased PPARγ sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE-H2S increased PPARγ activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE-H2S-mediated PPARγ activation might be a new therapeutic target for diabetes associated with obesity.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Physiology, Heibei University Health Science Center, PR China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Xianjuan
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China; Center for Noncoding RNA Medicine, Peking University Health Science Center, PR China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China; Center for Noncoding RNA Medicine, Peking University Health Science Center, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China.
authors.forename: Guoheng
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, PR China; Center for Noncoding RNA Medicine, Peking University Health Science Center, PR China; Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China. Electronic address: bingeng@hsc.pku.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Geng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D050156:Adipogenesis; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D014280:Triglycerides; D010727:Phosphoric Diester Hydrolases; D003542:Cystathionine gamma-Lyase; D005947:Glucose; D003545:Cysteine; D006862:Hydrogen Sulfide
keywords: Cystathionine γ lyase; Hydrogen sulfide; Obesity; Peroxisome proliferator-activated receptor γ; Phosphodiesterase; Sulfhydration