Cytokines promote lipolysis in 3T3-L1 adipocytes through induction of NADPH oxidase 3 expression and superoxide production

NADPH oxidase (NOX) enzymes are one of the major superoxide-generating systems in cells. NOX-generated superoxide has been suggested to promote insulin resistance in the liver. However, the role of NOX enzymes in mediating metabolic dysfunction in other insulin target tissues remains unclear. Here, we show that NOX3 expression is induced in differentiated 3T3-L1 adipocytes upon treatment with proinflammatory cytokines. Superoxide production increased concurrently with NOX3 protein expression in cytokine-treated adipocytes, which was inhibited by the NOX inhibitor diphenyleneiodonium (DPI). Treatment of adipocytes with cytokines increased lipolysis and decreased PPARγ activity. Interestingly, treatment with DPI blunted lipolysis activation by cytokines but failed to restore PPARγ activity. siRNA-mediated NOX3 downregulation also prevented cytokine-induced superoxide generation and lipolysis. In line with increasing lipolysis, cytokines increased the phosphorylation of hormone-sensitive lipase (HSL), which was reversed by treatment with DPI and silencing of NOX3 expression. We conclude that NOX3 is a cytokine-inducible superoxide-generating enzyme in adipocytes, which promotes lipolysis through increasing phosphorylation of HSL. This suggests a key role for NOX3-mediated superoxide production in the increased adipocyte lipolysis in inflammatory settings. NADPH oxidase (NOX) enzymes are one of the major superoxide-generating systems in cells. NOX-generated superoxide has been suggested to promote insulin resistance in the liver. However, the role of NOX enzymes in mediating metabolic dysfunction in other insulin target tissues remains unclear. Here, we show that NOX3 expression is induced in differentiated 3T3-L1 adipocytes upon treatment with proinflammatory cytokines. Superoxide production increased concurrently with NOX3 protein expression in cytokine-treated adipocytes, which was inhibited by the NOX inhibitor diphenyleneiodonium (DPI). Treatment of adipocytes with cytokines increased lipolysis and decreased PPARγ activity. Interestingly, treatment with DPI blunted lipolysis activation by cytokines but failed to restore PPARγ activity. siRNA-mediated NOX3 downregulation also prevented cytokine-induced superoxide generation and lipolysis. In line with increasing lipolysis, cytokines increased the phosphorylation of hormone-sensitive lipase (HSL), which was reversed by treatment with DPI and silencing of NOX3 expression. We conclude that NOX3 is a cytokine-inducible superoxide-generating enzyme in adipocytes, which promotes lipolysis through increasing phosphorylation of HSL. This suggests a key role for NOX3-mediated superoxide production in the increased adipocyte lipolysis in inflammatory settings. Adipose tissue is the major site of lipid turnover in the body. During fasting, triglyceride stores are broken down into FAs and glycerol through lipolysis (1.Monteiro R. Azevedo I. Chronic inflammation in obesity and the metabolic syndrome.Mediators Inflamm. 2010; 2010: 289645Crossref PubMed Scopus (693) Google Scholar). It has been established that adipose tissue lipolysis is altered in obesity and other inflammatory settings and that release of inflammatory cytokines by enlarged adipocytes or infiltrating immune cells impairs the activity of some key molecules involved in glucose and lipid metabolism (2.Guilherme A. Virbasius J.V. Puri V. Czech M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.Nat. Rev. Mol. Cell Biol. 2008; 9: 367-377Crossref PubMed Scopus (1601) Google Scholar, 3.Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (6121) Google Scholar, 4.Hotamisligil G.S. Arner P. Caro J.F. Atkinson R.L. Spiegelman B.M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.J. Clin. Invest. 1995; 95: 2409-2415Crossref PubMed Scopus (2960) Google Scholar). These include hormone-sensitive lipase (HSL), perilipin, and PPARγ (5.Penfornis P. Marette A. Inducible nitric oxide synthase modulates lipolysis in adipocytes.J. Lipid Res. 2005; 46: 135-142Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Reactive oxygen species (ROS) generated during inflammatory settings have been proposed to play a role in mediating insulin resistance and metabolic impairments in adipose tissue (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google Scholar, 7.Houstis N. Rosen E.D. Lander E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance.Nature. 2006; 440: 944-948Crossref PubMed Scopus (1955) Google Scholar). It is established that superoxide is overproduced in adipose tissue of obese animals (7.Houstis N. Rosen E.D. Lander E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance.Nature. 2006; 440: 944-948Crossref PubMed Scopus (1955) Google Scholar, 8.Talior I. Yarkoni M. Bashan N. Eldar-Finkelman H. Increased glucose uptake promotes oxidative stress and PKC-delta activation in adipocytes of obese, insulin-resistant mice.Am. J. Physiol. Endocrinol. Metab. 2003; 285: E295-E302Crossref PubMed Scopus (144) Google Scholar). Superoxide can be generated by enzymatic systems such as mitochondrial and peroxisomal pathways in fat cells, but the role of NADPH oxidases (NOXs) in the inflammatory obese state remains elusive. NOX enzymes are widely expressed in mammalian cells and belong to the family of flavocytochrome superoxide-producing enzymes (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google Scholar, 9.Lambeth J.D. NOX enzymes and the biology of reactive oxygen.Nat. Rev. Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2453) Google Scholar, 10.Ueno N. Takeya R. Miyano K. Kikuchi H. Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators.J. Biol. Chem. 2005; 280: 23328-23339Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The role of NOX, especially the prototypical NOX2 (also known as CGD91-phox), has been extensively studied in innate immunity (11.Guichard C. Moreau R. Pessayre D. Epperson T.K. Krause K.H. NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?.Biochem. Soc. Trans. 2008; 36: 920-929Crossref PubMed Scopus (103) Google Scholar). Other homologs of NOX2 have been identified, and these include: NOX1, NOX3, NOX4, NOX5, and DUOX1/DUOX2 (9.Lambeth J.D. NOX enzymes and the biology of reactive oxygen.Nat. Rev. Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2453) Google Scholar, 11.Guichard C. Moreau R. Pessayre D. Epperson T.K. Krause K.H. NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?.Biochem. Soc. Trans. 2008; 36: 920-929Crossref PubMed Scopus (103) Google Scholar). NOX3, a member of the NOX/dual-domain NOX family, has been first identified in specific portions of the middle ear (12.Bánfi B. Malgrange B. Knisz J. Steger K. Dubois-Dauphin M. Krause K.H. NOX3, a superoxide-generating NADPH oxidase of the inner ear.J. Biol. Chem. 2004; 279: 46065-46072Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar). NOX3 expression was previously reported in liver cells, where it has been shown to mediate TNFα-induced insulin resistance upon JNK activation (13.Li L. He Q. Huang X. Man Y. Zhou Y. Wang S. Wang J. Li J. NOX3-derived reactive oxygen species promote TNF-alpha-induced reductions in hepatocyte glycogen levels via a JNK pathway.FEBS Lett. 2010; 584: 995-1000Crossref PubMed Scopus (33) Google Scholar). Also, NOX3 is upregulated in the liver of obese mice, and treatment of hepatic cells with FFAs causes insulin resistance through increasing ROS production by NOX3 and activation of the p38 signaling pathway (14.Gao D. Nong S. Huang X. Lu Y. Zhao H. Lin Y. Man Y. Wang S. Yang J. Li J. The effects of palmitate on hepatic insulin resistance are mediated by NADPH oxidase 3-derived reactive oxygen species through JNK and p38MAPK pathways.J. Biol. Chem. 2010; 285: 29965-29973Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Because adipose tissue metabolism is severely impaired in inflammatory settings, we explored the role of NOX3 in adipocytes and its potential implication in cytokine-induced metabolic dysfunction. Our data show that NOX3 is rapidly induced upon cytokine exposure and that the subsequent increase in ROS production promotes lipolysis, which is linked to regulation of HSL phosphorylation. These results demonstrate a new role for NOX3 in regulating lipid metabolism in adipocytes. Cytokines were used at the following concentrations: TNFα (5 ng/ml; Fitzgerald, Concord, MA), IFN-γ (5,000 U/ml; RD Systems, Minneapolis, MN), and interleukin (IL)-1β (20 ng/ml; Sigma-Aldrich, St. Louis, MO) (15.Kapur S. Marcotte B. Marette A. Mechanism of adipose tissue iNOS induction in endotoxemia.Am. J. Physiol. 1999; 276: E635-E641PubMed Google Scholar). All cell culture solutions and supplements were purchased from Life Technologies, Inc., except for FBS, which was purchased from Sigma-Aldrich. Lipopolysaccharide (LPS) was purchased from Sigma-Aldrich. Reagents for SDS-PAGE and Western blot were from Bio-Rad (Hercules, CA) and Amersham (GE Healthcare Life Sciences, Mississauga, Canada). Goat polyclonal antibody against NOX3 was purchased from Santa Cruz Biotechnology (Paso Robles, CA). Rabbit monoclonal antibody against NOX4 was purchased from Epitomics (Burlingame, CA). Rabbit polyclonal antibodies against HSL, phospho-HSL (serine 563), and perilipin were purchased from Cell Signaling Technology (Beverly, MA), and FASN Ab was from Sigma-Aldrich. Secondary HRP-coupled antibodies were from Jackson Laboratories (West Grove, PA). NOX inhibitor diphenyleneiodonium (DPI) was used at a concentration of 10 μM (EMDMillipore). Nitroblue tetrazolium (NBT) chloride was purchased from Sigma; deoxy-d-glucose, 2-[1, 2-3H(N)] was from Perkin Elmer (Woodbridge, Canada). The 3T3-L1 fibroblasts were grown in α-DMEM (20% calf serum) and differentiated into adipocytes as previously described (5.Penfornis P. Marette A. Inducible nitric oxide synthase modulates lipolysis in adipocytes.J. Lipid Res. 2005; 46: 135-142Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Only cells showing at least 85% differentiation by morphological examination were used. Adipocytes were treated with a mixture of cytokines TNFα (5 ng/ml), IFN-γ (5,000 U/ml), and IL-1β (20 ng/ml) for either 8 or 24 h. Because transfection was found to affect the cytokine-induced ROS production, we have used a combination of cytokines plus LPS (1 µg/ml) in transfected adipocytes, in order to obtain similar ROS production to that of nontransfected cells. When DPI (10 μM) was used, it was added during the last hour of treatment, and control cells were treated with vehicle (DMSO, 1%). The 8- to 12-week-old C57BL/6J mice from our in-house colony were euthanized in accordance with our institutional guidelines. Epididymal fat (epididymal white adipose tissue) depot was removed under sterile conditions, and 50 µg of tissue from each mouse was directly placed in a culture plate with antibiotic-supplemented medium (DMEM low glucose and 10% FBS). Samples were incubated for 24 h before the medium was replaced and treatments performed as described for 3T3-L1 cells. All procedures were previously approved by the Laval University Animal Ethics Committee. Superoxide radicals were measured by the NBT reduction assay as described previously (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google Scholar, 16.Vrablic A.S. Albright C.D. Craciunescu C.N. Salganik R.I. Zeisel S.H. Altered mitochondrial function and overgeneration of reactive oxygen species precede the induction of apoptosis by 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine in p53-defective hepatocytes.FASEB J. 2001; 15: 1739-1744Crossref PubMed Scopus (122) Google Scholar). In brief, during the last hour of treatment, NBT (1%) was added to the cells and incubated at 37°C. Then, the incubation medium was removed, the cells were sonicated in of and the of NBT was measured at were in and protein was measured by the protein assay of of was in on and to were with plus and incubated at with antibodies in by incubation for h at with HRP-coupled were incubation with were the was as Canada). was performed the was with St. and was performed on a Mississauga, Canada). Nox3 and The 3T3-L1 adipocytes were of for h and incubated in with with or cytokines. The last hour of treatment, medium was added with or cytokines and other glycerol was measured the enzymatic as previously described (5.Penfornis P. Marette A. Inducible nitric oxide synthase modulates lipolysis in adipocytes.J. Lipid Res. 2005; 46: 135-142Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The 3T3-L1 adipocytes were grown and differentiated as previously differentiated adipocytes were treated with cytokines for 24 h. concentration of 10 μM DPI inhibitor or vehicle was added during the last hour of the were and 10 was for activity as described by the In brief, were on a plate with a the h incubation at the were and a antibody against PPARγ was added for h at antibody to was added to a at The results were for protein in 10 of 3T3-L1 adipocytes were treated with cytokines for a of 24 h. were h to glucose and treatments were by cytokines. and DPI or vehicle were added for the last hour of treatment at in the were with uptake was measured by glucose (1 in for 8 and medium was to cells with were in 50 and to 2 of for a concentration in cell was protein assay The 3T3-L1 adipocytes were transfected with a transfection transfection of adipocytes in 4: PubMed Scopus Google Scholar). differentiated 3T3-L1 adipocytes were at in a and previously with was added to the cells. cells were transfected with 24 h cells where treated with cytokines and for the of NOX3 protein expression by Western The effects of the treatments were by or All data are as were to be at Treatment of differentiated 3T3-L1 adipocytes with proinflammatory cytokines and to a increase in superoxide production This was in adipocytes that and TNFα can increase superoxide production but we have to a combination of cytokines to the known proinflammatory of the of NOX to ROS production in 3T3-L1 adipocytes, we have a inhibitor of of enzymes N. Takeya R. Miyano K. Kikuchi H. Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators.J. Biol. Chem. 2005; 280: 23328-23339Abstract Full Text Full Text PDF PubMed Scopus (149) Google the generation of shown in DPI superoxide production measured 8 or 24 h in 3T3-L1 adipocytes. cytokine treatment also increased ROS production in adipose which was also inhibited by treatment with DPI These data that NOX enzymes are the of superoxide production in cytokine-treated adipocytes and in adipose The NOX family of N. Takeya R. Miyano K. Kikuchi H. Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators.J. Biol. Chem. 2005; 280: 23328-23339Abstract Full Text Full Text PDF PubMed Scopus (149) Google and it has been shown that NOX4 is expressed in adipocytes, where it role in adipocyte differentiation N. J. I. H. A. and regulation of insulin signaling by reactive oxygen and Rev. PubMed Scopus Google Scholar, S. Wang M. S. Steger K. M. P. expression of the NADPH oxidase NOX4 is a of adipocyte PubMed Scopus Google Scholar). 3T3-L1 fibroblasts and differentiated 3T3-L1 adipocytes Nox3 and differentiated 3T3-L1 cells expressed NOX3 and NOX4 that expression is at the NOX4 is constitutively expressed in adipose cells, its expression was increased by treatment with cytokines Li (13.Li L. He Q. Huang X. Man Y. Zhou Y. Wang S. Wang J. Li J. NOX3-derived reactive oxygen species promote TNF-alpha-induced reductions in hepatocyte glycogen levels via a JNK pathway.FEBS Lett. 2010; 584: 995-1000Crossref PubMed Scopus (33) Google have shown that cytokine treatment of to increased expression of We NOX3 protein expression in adipocytes and found that it was induced 8 h exposure to cytokines and to 24 h treatment DPI affect NOX3 protein expression. We also a increase of NOX3 expression in adipose treated with cytokines for 24 h These results show that NOX3 protein expression is also in adipocytes and to superoxide production in cytokine-treated cells. We NOX3 was involved in superoxide siRNA-mediated was found to NOX3 expression by in cytokine-treated cells as with a control NOX4 expression was by NOX3 NOX3 was to cytokine-induced superoxide generation but affect ROS production, to a low expression of NOX3 in cells. These results that NOX3 is for the increase in superoxide production in cytokine-treated adipocytes. ROS play role as signaling molecules in the regulation of and differentiation and regulation C. K. S. N. production, and activation of Biol. 2004; PubMed Scopus Google Scholar, J.F. T. Reactive oxygen species of lipase to the lipid during lipolysis in human differentiated PubMed Scopus Google Scholar, K. K. I. as a differentiation and in Biol. PubMed Scopus Google Scholar). Interestingly, it has been suggested that ROS generated from NOX increase lipolysis in human adipocytes J.F. T. Reactive oxygen species of lipase to the lipid during lipolysis in human differentiated PubMed Scopus Google Scholar). the of NOX-generated ROS on metabolic in adipocytes, we the of superoxide production with DPI on lipolysis by the release of We that cytokine treatment increased lipolysis and to levels to a 2 h treatment with This increase in lipolysis by cytokines was also in adipose In the induction in lipolysis in to cytokines was prevented by DPI the that superoxide production promotes lipolysis through regulating HSL, one of the enzymes triglyceride in adipocytes, we the of DPI on HSL phosphorylation on which is in the activation of the enzyme (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google Scholar, J.F. T. Reactive oxygen species of lipase to the lipid during lipolysis in human differentiated PubMed Scopus Google Scholar, L. C. C. of phosphorylation in hormone-sensitive lipase that are in to and activation in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.P. of and adipocyte lipolysis by PubMed Scopus Google Scholar, of HSL phosphorylation in and adipose J. Physiol. Endocrinol. Metab. 2006; PubMed Scopus Google Scholar). We found that cytokine exposure increased phosphorylation of HSL at 8 h and that was by DPI Interestingly, cytokines affect perilipin expression at the but its levels by 24 h that phosphorylation of HSL the downregulation of perilipin in cytokine-treated adipocytes Because ROS have also been shown to glucose uptake in adipocytes H. K. H. M. R. M. Y. H. K. reactive oxygen species (ROS) production and glucose uptake via ROS in Res. 2010; PubMed Scopus Google and to PPARγ activity (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google we NOX also modulates these metabolic pathways in cytokine-treated adipocytes. we that cytokine treatment decreased PPARγ was reversed by DPI Also, was by DPI that ROS production by is lipolysis in adipocytes. Because DPI reversed the of cytokines on lipolysis and decreased phosphorylation of HSL on we NOX3 was lipolysis was prevented by siRNA-mediated of NOX3, similar to the of DPI treatment of NOX3 was found to HSL phosphorylation on 8 h exposure to which was similar to the of DPI These results are with a superoxide generation from NOX3 to lipolysis by increasing phosphorylation of HSL in adipocytes. is a inflammatory with insulin resistance and metabolic that to the inflammation is by increased expression of proinflammatory cytokines by infiltrating immune cells in adipose tissue G.S. inflammatory in adipose Clin. Invest. 2003; PubMed Scopus Google Scholar). linking inflammation to the of insulin resistance have been and involved ROS and reactive species (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google Scholar, G.S. and metabolic 2006; PubMed Scopus Google Scholar, type a of the innate immune PubMed Scopus Google Scholar, G.S. and Clin. Invest. 2005; PubMed Scopus Google Scholar, A. Marette A. of protein and lipid signaling molecules by reactive J. Physiol. Endocrinol. Metab. 2010; PubMed Scopus Google Scholar). We have previously the role of production in insulin resistance in and liver through A. Marette A. Inducible nitric oxide synthase induction hepatic insulin resistance in potential role of of insulin signaling 2010; PubMed Scopus Google Scholar, S. S. Marcotte B. Marette A. of nitric oxide synthase in a role for nitric oxide as a of insulin 46: PubMed Scopus Google Scholar, M. Marette A. of nitric oxide synthase against obesity-linked insulin resistance in 2001; PubMed Scopus Google Scholar, A. P. M. S. Marette A. induction causes insulin resistance via induced of in 2010; PubMed Scopus Google Scholar). Because is from the of with it is to the major superoxide-producing systems that metabolic under inflammatory (6.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J. Clin. Invest. 2004; 114: 1752-1761Crossref PubMed Scopus (4000) Google have shown that ROS are increased in adipose tissue of a mouse of obesity and This increase in ROS generation was by increase in NOX activation and NOX4 expression. also that treatment of adipocytes with FAs increased oxidative stress via NOX with altered adipocyte function and and PPARγ expression. Here, we show that under inflammatory settings, superoxide production was increased in adipocytes to the induction of NOX3 to activation of lipolysis, reversed by siRNA-mediated of NOX3 or by of NOX with Interestingly, it has been shown that in differentiated human adipocytes, lipolysis was inhibited in the of DPI by the of HSL to the lipid J.F. T. Reactive oxygen species of lipase to the lipid during lipolysis in human differentiated PubMed Scopus Google Scholar). J.F. T. Reactive oxygen species of lipase to the lipid during lipolysis in human differentiated PubMed Scopus Google have shown that in human adipocytes, DPI decreased the phosphorylation of HSL on which to in with these we found that inflammatory cytokines increased the phosphorylation of HSL on and that was reversed by DPI treatment, as as by NOX3 These results are with a major role for NOX3 in superoxide production upon cytokine treatment, to activation in adipocytes via the pathway and also be the activation and lipolysis. Our NOX3 as a key of adipocyte metabolism under inflammatory This was siRNA-mediated of NOX3 and by the NOX inhibitor have on NOX4, which is expressed in adipocytes and to play a role in adipocyte differentiation and in insulin S. Wang M. S. Steger K. M. P. expression of the NADPH oxidase NOX4 is a of adipocyte PubMed Scopus Google Scholar, K. K. I. as a differentiation and in Biol. PubMed Scopus Google Scholar, K. H. X. J.D. The oxidase modulates generation of and role in insulin Biol. 2004; PubMed Scopus Google Scholar). we have NOX4 expression in adipocytes, its expression was by cytokine of NOX3 was to cytokine-induced superoxide production, that NOX3 is a major superoxide-generating NOX in adipocytes to inflammatory NOX4 is known to superoxide with NOX3, which superoxide Y. D. J.D. a oxygen PubMed Scopus Google Scholar). ROS generated from these enzymes are effects on through Our results are with a major role of NOX3 in superoxide in inflammatory settings. PPARγ is of adipocyte differentiation and lipid and it has been shown that inflammation modulates PPARγ activity in adipose tissue P. K. M. S. C. P. J. mice nitric oxide synthase are to the metabolic of 2008; PubMed Scopus Google Scholar). We NOX3 also be involved in the regulation of Interestingly, DPI decreased PPARγ activity in cells, it its impaired activity in cytokine-treated adipocytes. These data are in accordance with our that PPARγ is by by and that superoxide generation is for of PPARγ in the inflammatory of obesity P. K. M. S. C. P. J. mice nitric oxide synthase are to the metabolic of 2008; PubMed Scopus Google Scholar). In we found that NOX3 is NOX that a role in lipolysis under inflammatory settings. NOX3 to lipolysis through regulating HSL phosphorylation on by a that remains to be are to the role of NOX3 in mediating of adipose tissue lipolysis in under inflammatory settings such as of the that NOX3 induction to activation in adipocytes new potential to lipolysis in diphenyleneiodonium hormone-sensitive lipase interleukin Nitroblue tetrazolium NADPH oxidase reactive oxygen species

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