Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
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
Graphical abstract
Introduction
Obesity is a prevalent health hazard and is characterized by adipose tissue expansion due to increasing number of cells via adipocyte differentiation (hyperplasia) and large adipocyte size (hypertrophy) [1]. Obesity is associated with an increase in circulating levels of several amino acids such as homocysteine, cysteine, alanine, phenylalanine, and tyrosine [2], [3], [4], [5]. Cysteine is a metabolic product of the essential amino acid methionine and is synthesized by transsulfuration from homocysteine dependent on cystathionine β synthase (CBS) and cystathionine γ lyase (CSE) [6]. Several large epidemiological studies showed plasma total cysteine (tCys) positively associated with body mass index [2], [7], [8]. However, in animals or humans, intake of cysteine-rich protein did not increase fat mass [9]. Knockout of CBS [10] can reduce body and adipose tissue weight. In humans, homocysteinuria due to CBS deficiency [11] or CSE mutation [12] was associated with lipodystrophy; in contrast, Down's syndrome children with high CBS activity [13] exhibit obesity. Thus, endogenous cysteine biogenesis enzymes but not cysteine per se may be linked with obesity.
CSE is a key enzyme generating cysteine by hydrolyzing cystathionine. CSE and CBS also hydrolyze cysteine to produce hydrogen sulfide (H2S) [6]. Feeding CSE-knockout mice with cysteine-limited food decreased white adipose weight about two thirds as compared with wild-type mice [14], so the CSE–H2S system might be involved in the pathogenesis of obesity. Our previous work found that adipocytes expressed CSE and endogenously generated H2S [15], [16]; the CSE inhibitor dl-propargylglycine (PPG) increased lipolysis in adipocytes and blocked obesity induced by a high-fat diet (HFD) [17]. Thus, the CSE–H2S system affects adipocyte hypertrophy by regulating lipolysis during obesity. Recently, Tsai et al. reported that H2S promotes adipogenesis [18], so H2S might increase adipocyte hyperplasia causing obesity. H2S increased insulin sensitivity in adipocytes with high glucose treatment [19], TNF-α [20] or diabetic mice induced by an HFD [17]. Whether CSE/H2S promotes glucose utility to storage in lipid droplets in adipocytes is unknown as is its possible molecular mechanism.
In the present study, we investigated the CSE–H2S effects on exchange of glucose to triglycerides by sulfhydating peroxisome proliferator-activated receptor γ (PPARγ) in adipocytes.
Section snippets
Animals and materials
All animal procedures complied with the Animal Management Rule of the Ministry of Health, People's Republic of China (document no. 55, 2001) and the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, updated 2011). The care and use of laboratory animals were approved by the Laboratory Animal Ethics Committee of Peking University. A total of 75 C57BL/6J mice (18–20 g, 10 weeks old) were supplied by the Animal Center, Peking University
CSE–H2S system promoted triglyceride accumulation in adipocyte differentiation
3T3L1 preadipocytes expressed CSE mRNA (Fig. S1A) and protein (Fig. S1B), which was upregulated during differentiation into mature adipocytes (Fig. S1A and C, all P < 0.01). Consistent with changes in CSE expression, H2S production was significantly increased during adipocyte differentiation (Fig. S1D). Thus, the CSE–H2S system was upregulated in adipocyte differentiation.
Treating 3T3L1 preadipocytes in the differentiation cocktail with dl-propargylglycine (PPG, 100 μM; the CSE inhibitor)
Discussion
CSE is a key enzyme to catalyze cystathionine generation l-cysteine, concomitantly releasing H2S [6]. CSE-knockout mice fed an l-cysteine-deficient diet showed white fat loss [14]. In contrast, HFD feeding lowered CSE protein expression and H2S production [17]. Therefore, adipocyte CSE–H2S system dysfunction may contribute to obesity. Obese adipocytes are always associated with impaired insulin sensitivity. Interestingly, high glucose downregulated the CSE–H2S system [27], whereas H2S increased
Conflicts of interest
The authors declare no conflicts of interest.
Transparency document
Acknowledgments
This work was supported by the Major State Basic Research Development Program of the People's Republic of China (no. 2012CB517806) and the National Natural Science Foundation of China (nos. 81170235, 81470552, 91339106 and 91439119).
References (43)
- et al.
Lifestyle and cardiovascular disease risk factors as determinants of total cysteine in plasma: the Hordaland Homocysteine Study
Am. J. Clin. Nutr.
(1999) - et al.
A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance
Cell Metab.
(2009) - et al.
Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism?
Am. J. Clin. Nutr.
(2008) - et al.
Homocysteine metabolism in children with down syndrome: in vitro modulation
Am. J. Hum. Genet.
(2001) - et al.
A critical life-supporting role for cystathionine gamma-lyase in the absence of dietary cysteine supply
Free Radic. Biol. Med.
(2011) - et al.
Hydrogen sulfide from adipose tissue is a novel insulin resistance regulator
Biochem. Biophys. Res. Commun.
(2009) - et al.
Hydrogen sulfide and l-cysteine increase phosphatidylinositol 3,4,5-trisphosphate (PIP3) and glucose utilization by inhibiting phosphatase and tensin homolog (PTEN) protein and activating phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT)/protein kinase Czeta/lambda (PKCzeta/lambda) in 3T3l1 adipocytes
J. Biol. Chem.
(2011) - et al.
Fluorometric quantification of DNA in cells and tissue
Anal. Biochem.
(1983) - et al.
Klotho is a target gene of PPAR-gamma
Kidney Int.
(2008) - et al.
Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets
J. Biol. Chem.
(1991)
Vitamin D up-regulates glucose transporter 4 (GLUT4) translocation and glucose utilization mediated by cystathionine-gamma-lyase (CSE) activation and H2S formation in 3T3L1 adipocytes
J. Biol. Chem.
Development of hormone receptors and hormonal responsiveness in vitro. insulin receptors and insulin sensitivity in the preadipocyte and adipocyte forms of 3T3-L1 cells
J. Biol. Chem.
Regulating adipogenesis
J. Biol. Chem.
15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma
Cell
Role of free fatty acid receptors in the regulation of energy metabolism
Biochim. Biophys. Acta
The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences
Clin. Chem.
Sex differences in the effect of obesity on human plasma tryptophan/large neutral amino acid ratio
Ann. Nutr. Metab.
Splanchnic glucose and amino acid metabolism in obesity
J. Clin. Invest.
Endogenous production of hydrogen sulfide in mammals
Amino Acids
The association of plasma cysteine and gamma-glutamyltransferase with BMI and obesity
Obesity (Silver Spring)
Cysteine and obesity
Obesity (Silver Spring)
Cited by (0)
- 1
These authors contributed equally to this work.