Regulation of the nitric oxide system in human adipose tissue

Nitric oxide (NO) is involved in adipose tissue biology by influencing adipogenesis, insulin-stimulated glucose uptake, and lipolysis. The enzymes responsible for NO formation in adipose cells are endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), whereas neuronal NO synthase (bNOS) is not expressed in adipocytes. We characterized the expression pattern and the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human subcutaneous adipose cells by combining in vivo and in vitro studies. Expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes was detected. In vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced. The genes encoding eNOS, iNOS, and cGMP-dependent protein kinase 1 were expressed at higher levels in obese women. Expression of these genes, however, was not influenced by 5% weight loss. Insulin and angiotensin II (Ang II) increased NO production by human preadipocytes in vitro.Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity. Nitric oxide (NO) is involved in adipose tissue biology by influencing adipogenesis, insulin-stimulated glucose uptake, and lipolysis. The enzymes responsible for NO formation in adipose cells are endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), whereas neuronal NO synthase (bNOS) is not expressed in adipocytes. We characterized the expression pattern and the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human subcutaneous adipose cells by combining in vivo and in vitro studies. Expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes was detected. In vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced. The genes encoding eNOS, iNOS, and cGMP-dependent protein kinase 1 were expressed at higher levels in obese women. Expression of these genes, however, was not influenced by 5% weight loss. Insulin and angiotensin II (Ang II) increased NO production by human preadipocytes in vitro. Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity. Nitric oxide (NO) is a vasodilator with a short half-life of 3–5 s. NO acts within a small distance of ∼1.5 nm and is thus ideally suited to act as a tissue hormone (1Ignarro L.J. Physiology and pathophysiology of nitric oxide.Kidney Int. Suppl. 1996; 55: 2-5Google Scholar). Enzymes responsible for NO formation by rat and human adipose cells are the membrane-bound endothelial NO synthase (eNOS) and the cytoplasmically localized inducible NO synthase (iNOS) (2Nisoli E. Tonello C. Briscini L. Carruba M.O. Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue.Endocrinology. 1997; 138: 676-682Google Scholar, 3Kapur S. Marcotte B. Marette A. Mechanism of adipose tissue iNOS induction in endotoxemia.Am. J. Physiol. 1999; 276: E635-E641Google Scholar, 4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 5Ribiere C. Jaubert A.M. Gaudiot N. Sabourault D. Marcus M.L. Boucher J.L. Denis-Henriot D. Giudicelli Y. White adipose tissue nitric oxide synthase: a potential source for NO production.Biochem. Biophys. Res. Commun. 1996; 222: 706-712Google Scholar, 6Elizalde M. Ryden M. van Harmelen V. Eneroth P. Gyllenhammar H. Holm C. Ramel S. Olund A. Arner P. Andersson K. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans.J. Lipid Res. 2000; 41: 1244-1251Google Scholar). In vitro, NO inhibits proliferation and stimulates the expression of two adipogenic marker genes, peroxisome proliferator-activated receptor γ and uncoupling protein 1, in rat brown preadipocytes (7Nisoli E. Clementi E. Tonello C. Sciorati C. Briscini L. Carruba M.O. Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures.Br. J. Pharmacol. 1998; 125: 888-894Google Scholar). Lipid accumulation and lipogenic enzymes are also induced by NO in rat white preadipocytes (8Yan H. Aziz E. Shillabeer G. Wong A. Shanghavi D. Kermouni A. Abdel-Hafez M. Lau D.C. Nitric oxide promotes differentiation of rat white preadipocytes in culture.J. Lipid Res. 2002; 43: 2123-2129Google Scholar). Whereas increased NO formation may contribute to cold-associated vasodilation in brown adipose tissue in rats (2Nisoli E. Tonello C. Briscini L. Carruba M.O. Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue.Endocrinology. 1997; 138: 676-682Google Scholar, 9Nagashima T. Ohinata H. Kuroshima A. Involvement of nitric oxide in noradrenaline-induced increase in blood flow through brown adipose tissue.Life Sci. 1994; 54: 17-25Google Scholar), microdialysis measurements revealed that inhibition of NO synthesis does not influence adipose tissue blood flow in humans (4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 10Jordan J. Tank J. Stoffels M. Franke G. Christensen N.J. Luft F.C. Boschmann M. Interaction between β-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism.J. Clin. Endocrinol. Metab. 2001; 86: 2803-2810Google Scholar, 11Boschmann M. Jordan J. Adams F. Christensen N.J. Tank J. Franke G. Stoffels M. Sharma A.M. Luft F.C. Klaus S. Tissue-specific response to interstitial angiotensin II in humans.Hypertension. 2003; 41: 37-41Google Scholar). Blocking NO synthesis abolished the cGMP-dependent suppressive effect of tumor necrosis factor-α on lipoprotein lipase activity in mouse brown adipocytes (12Uchida Y. Tsukahara F. Ohba K. Ogawa A. Irie K. Fujii E. Yoshimoto T. Yoshioka T. Muraki T. Nitric oxide mediates down regulation of lipoprotein lipase activity induced by tumor necrosis factor-alpha in brown adipocytes.Eur. J. Pharmacol. 1997; 335: 235-243Google Scholar). In vivo, insulin-stimulated glucose uptake in rat white adipose tissue was dependent on intact NO synthesis (13Roy D. Perreault M. Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.Am. J. Physiol. 1998; 274: E692-E699Google Scholar). Basal as well as catecholamine-stimulated lipolysis were inhibited by NO in human and rat subcutaneous adipose tissue depots (4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 10Jordan J. Tank J. Stoffels M. Franke G. Christensen N.J. Luft F.C. Boschmann M. Interaction between β-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism.J. Clin. Endocrinol. Metab. 2001; 86: 2803-2810Google Scholar, 11Boschmann M. Jordan J. Adams F. Christensen N.J. Tank J. Franke G. Stoffels M. Sharma A.M. Luft F.C. Klaus S. Tissue-specific response to interstitial angiotensin II in humans.Hypertension. 2003; 41: 37-41Google Scholar, 14Gaudiot N. Jaubert A.M. Charbonnier E. Sabourault D. Lacasa D. Giudicelli Y. Ribiere C. Modulation of white adipose tissue lipolysis by nitric oxide.J. Biol. Chem. 1998; 273: 13475-13481Google Scholar, 15Klatt P. Cacho J. Crespo M.D. Herrera E. Ramos P. Nitric oxide inhibits isoproterenol-stimulated adipocyte lipolysis through oxidative inactivation of the beta-agonist.Biochem. J. 2000; 351: 485-493Google Scholar). Based on these findings, NO appears to be an important mediator of adipocyte physiology with lipogenic properties. Cytokine-dependent regulation of iNOS has already been described in fat cells (3Kapur S. Marcotte B. Marette A. Mechanism of adipose tissue iNOS induction in endotoxemia.Am. J. Physiol. 1999; 276: E635-E641Google Scholar, 5Ribiere C. Jaubert A.M. Gaudiot N. Sabourault D. Marcus M.L. Boucher J.L. Denis-Henriot D. Giudicelli Y. White adipose tissue nitric oxide synthase: a potential source for NO production.Biochem. Biophys. Res. Commun. 1996; 222: 706-712Google Scholar, 16Pilon G. Penfornis P. Marette A. Nitric oxide production by adipocytes: a role in the pathogenesis of insulin resistance?.Horm. Metab. Res. 2000; 32: 480-484Google Scholar), and characterized the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human adipose with known effects on adipocytes are insulin and angiotensin II (Ang II) and insulin Clin. 2000; Scholar, S. P. K. Boschmann M. J. G. M. F. Sharma A.M. The role in the J. Biol. 2003; Scholar). both are known of eNOS activity in endothelial cells H. II stimulates synthesis of endothelial nitric oxide 1998; Scholar, K. N. M. T. of endothelial nitric oxide synthase expression in endothelial cells and in a of 2001; Scholar), also the influence of insulin and Ang II on eNOS activity in human adipose adipocytes and preadipocytes for in vitro were isolated subcutaneous adipose tissue as described J. S. K. Luft F.C. Sharma A.M. adipocytes in vitro differentiation of human preadipocytes angiotensin 1 2002; Scholar). In adipose tissue was small of blood and for 1 at at The was through a and for at in a and adipocytes. 1 of adipocytes were with at for and increased the of the adipocyte as cells and were adipocytes J. S. K. Luft F.C. Sharma A.M. adipocytes in vitro differentiation of human preadipocytes angiotensin 1 2002; Scholar). adipose tissue these were also and were for expression to the tissue with of adipocytes. of adipose tissue were in of blood and and to for at by a at The was in adipocyte through a and The cells were to the in was induced by the of 1 1 and were to the adipose as by with J. S. K. Luft F.C. Sharma A.M. adipocytes in vitro differentiation of human preadipocytes angiotensin 1 2002; Scholar), was in of the cells at expression preadipocytes were with and at and for these were and were as described J. S. K. Luft F.C. Sharma A.M. expression in human adipocytes is not to insulin Res. 2002; Scholar). In was isolated by the the by the of and with the and the of was in for 1 at of of and expression of NO system genes were revealed by of isolated of adipose tissue and adipocytes the not the in were the as for the of expression with the system were on and were to of expression was with the system for the as described J. S. K. Luft F.C. Sharma A.M. expression in human adipocytes is not to insulin Res. 2002; Scholar). as the as small in expression the described in K. J. S. Sharma A.M. of for expression in human adipocytes and Metab. Res. 2001; Scholar). were with the and the for in a of of and for NO system genes are in The were at at and of at and 1 at of were for eNOS and iNOS, for guanylate for cGMP-dependent protein kinase 1 and for of and to expression of NO system genes in human adipose NO NO NO of of of protein kinase protein kinase neuronal NO nitric between and of and are in the are with and with soluble guanylate in a neuronal NO nitric between and of and are in the are with and with soluble guanylate the of eNOS human preadipocytes were isolated as described the cells were the and with and the was and with 1 insulin 1 Ang II was for NO measurements of NO was by in the the the of of by D. S. H. C. K. J. of and in by and by the with the by 1997; Scholar). A was to the at NO formation was by the protein of the and the are as the increase of with the were eNOS activity is dependent on the influence of Ang II on in human primary preadipocytes were in a system in the were with for at and with 1 Ang preadipocytes were in and in for at to was with a system with and The two were by the and was In the as 1 with of were in the two of these for two of increased with levels of the and were on was at the of and was hormone an measurements were at by a blood was for and to of subcutaneous adipose tissue was the by local with were isolated the by as described and were in for expression the Insulin was on glucose and insulin levels in blood at G. G. A. of of insulin implications for Clin. Endocrinol. Metab. 2001; 86: Scholar). and were by with was by blood 1 the A of was for and was for were and In the a weight by a to by and measurements were to in the and adipose tissue were the weight and at the 5% weight loss been was the In expression was in the adipose tissue and not in isolated adipocytes. was at the and hormone in was the and were Ang and were and and were and was The and were and were were by and the and for were The and the were for NO measurements were and and was The are as as and as and in and between was by and as production by for two by the for loss and by the for dependent vitro In the a was for that the of insulin and the of blood as were at In in the pattern of expression of NO system genes was between between adipose tissue and isolated adipocytes two human adipocytes expressed both the eNOS and iNOS genes not the encoding the neuronal NO synthase (bNOS) NO to the soluble guanylate cyclase, and that adipocytes two genes encoding and and encoding a The of the soluble guanylate by NO in the formation of the the cGMP-dependent protein and both known human genes and were expressed in human adipocytes. were not to in the expression level of eNOS was higher that of iNOS, both in adipose tissue and in isolated adipocytes. for eNOS and iNOS were in of isolated human adipocytes by the The for is in The of to a expression level of eNOS with of in vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced by in the and iNOS expression the of in vitro expression are expressed as the for eNOS iNOS at and by within the at the of the between the and and are and were by the for dependent with In the were and by and obese the most important of these women. Expression of NO system genes was in isolated adipocytes subcutaneous adipose tissue in revealed that the genes encoding eNOS, iNOS, and were expressed at higher levels in the obese whereas the was expressed at levels in and obese the and obese were not with to also in a was for of these genes that of insulin and the blood as eNOS, iNOS, and expression was to blood was of and revealed for the The of the for eNOS were and for the and and for blood The of the for iNOS were and for the and and for blood The of the for were and for the and and for blood of the obese for two obese for two obese for two obese for two obese for two obese for two of measurements obese for two of measurements obese for two of insulin obese for two obese for two obese for two were and were by and are as blood obese for two in a were and were by and are as blood loss of 5% in the of increased insulin and the blood by Expression of the genes, however, was not influenced by weight loss of weight loss on in for for of measurements for of measurements of insulin for for expression expression expression expression are as and of the was and the to 5% weight loss was for in a are as and of the was and the to 5% weight loss was of isolated human preadipocytes with insulin Ang II in a increase of NO formation with preadipocytes by to the increase of NO by protein of the and with preadipocytes insulin and Ang II are known of eNOS and the increase in eNOS activity Ang II stimulation in endothelial cells is to the increased of and that Ang II a increase of in human of a is also in and the of cells of revealed a and to increase of in human preadipocytes stimulation with Ang In the expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes. on the expression of eNOS and iNOS, not in human adipocytes are in with (2Nisoli E. Tonello C. Briscini L. Carruba M.O. Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue.Endocrinology. 1997; 138: 676-682Google Scholar, 3Kapur S. Marcotte B. Marette A. Mechanism of adipose tissue iNOS induction in endotoxemia.Am. J. Physiol. 1999; 276: E635-E641Google Scholar, 4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 5Ribiere C. Jaubert A.M. Gaudiot N. Sabourault D. Marcus M.L. Boucher J.L. Denis-Henriot D. Giudicelli Y. White adipose tissue nitric oxide synthase: a potential source for NO production.Biochem. Biophys. Res. Commun. 1996; 222: 706-712Google Scholar, 6Elizalde M. Ryden M. van Harmelen V. Eneroth P. Gyllenhammar H. Holm C. Ramel S. Olund A. Arner P. Andersson K. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans.J. Lipid Res. 2000; 41: 1244-1251Google Scholar, M. Elizalde M. van Harmelen V. A. J. S. Andersson K. Increased expression of eNOS protein in subcutaneous adipose tissue in obese human J. 2001; Scholar), and these to of the NO NO to the soluble guanylate cyclase, a two subunits M. D. of 2002; Scholar). the human genes known to these adipocytes two genes encoding and and encoding a The of the soluble guanylate by NO in the formation of the the cGMP-dependent protein kinase by cGMP-dependent protein 1996; Scholar). by two genes are known and and both were expressed in human adipocytes. Based on expression NO in human adipose cells to in tissues (1Ignarro L.J. Physiology and pathophysiology of nitric oxide.Kidney Int. Suppl. 1996; 55: 2-5Google Scholar, M. D. of 2002; Scholar, by cGMP-dependent protein 1996; Scholar), thus the effects of NO in human adipose tissue isolated adipocytes (4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 11Boschmann M. Jordan J. Adams F. Christensen N.J. Tank J. Franke G. Stoffels M. Sharma A.M. Luft F.C. Klaus S. Tissue-specific response to interstitial angiotensin II in humans.Hypertension. 2003; 41: 37-41Google Scholar). M. Ryden M. van Harmelen V. Eneroth P. Gyllenhammar H. Holm C. Ramel S. Olund A. Arner P. Andersson K. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans.J. Lipid Res. 2000; 41: 1244-1251Google Scholar, M. Elizalde M. van Harmelen V. A. J. S. Andersson K. Increased expression of eNOS protein in subcutaneous adipose tissue in obese human J. 2001; described higher and protein expression levels of eNOS with iNOS within human adipose tissue of We in isolated human adipocytes of women. eNOS appears to be the NO synthase in human adipose eNOS expression not increase in vitro adipogenesis, that eNOS activity already to preadipocytes and adipocytes been to NO (8Yan H. Aziz E. Shillabeer G. Wong A. Shanghavi D. Kermouni A. Abdel-Hafez M. Lau D.C. Nitric oxide promotes differentiation of rat white preadipocytes in culture.J. Lipid Res. 2002; 43: 2123-2129Google Scholar, C. Jaubert A.M. Sabourault D. Lacasa D. Giudicelli Y. Insulin stimulates nitric oxide production in rat Biophys. Res. Commun. 2002; Scholar). The that both insulin and Ang II NO production in human preadipocytes in the of eNOS as an important NO synthase in human adipose Insulin and Ang II been to eNOS expression in endothelial cells H. II stimulates synthesis of endothelial nitric oxide 1998; Scholar, K. N. M. T. of endothelial nitric oxide synthase expression in endothelial cells and in a of 2001; a mechanism may contribute to increased NO formation in Insulin and Ang however, are also of eNOS in endothelial as Ang II and insulin the of eNOS through the of and protein In to the effects of insulin in rat adipocytes on NO formation C. Jaubert A.M. Sabourault D. Lacasa D. Giudicelli Y. Insulin stimulates nitric oxide production in rat Biophys. Res. Commun. 2002; Scholar), that Ang II in a increase in in human and of Ang II insulin may act to increase NO NO has a role in the regulation of the influence of and insulin on the adipose NO system is of In of eNOS and iNOS genes was in isolated subcutaneous by increased expression of the encoding cGMP-dependent protein kinase by Elizalde M. Ryden M. van Harmelen V. Eneroth P. Gyllenhammar H. Holm C. Ramel S. Olund A. Arner P. Andersson K. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans.J. Lipid Res. 2000; 41: 1244-1251Google on eNOS expression in adipose In to however, also an increase in iNOS expression in obese may be to the that isolated whereas adipose We the that increased iNOS expression the of is that of iNOS expression be in the obese to an between eNOS and iNOS expression were to is that increased iNOS expression to to is to that the expression of the the in vivo increased iNOS expression has been described in white adipose tissue of as well as of M. Marette A. of inducible nitric oxide synthase insulin in 2001; Scholar). We a increase in eNOS, iNOS, and expression in the obese revealed blood as the to the increased expression of these The between and however, is well and contribute to in the most be that the of higher of and increased blood to increased expression of these genes in obesity. In of may an of the pathophysiology of obesity. of adipocyte expression may contribute to increased eNOS and iNOS the influence of insulin and Ang II on eNOS expression in endothelial cells is well known H. II stimulates synthesis of endothelial nitric oxide 1998; Scholar, K. N. M. T. of endothelial nitric oxide synthase expression in endothelial cells and in a of 2001; Scholar, D. J. T. K. S. M. The role of endothelial insulin in the regulation of and insulin Clin. 2003; Scholar). C. Jaubert A.M. Sabourault D. Lacasa D. Giudicelli Y. Insulin stimulates nitric oxide production in rat Biophys. Res. Commun. 2002; and increased local production of Ang II K. S. J. Luft F.C. Sharma A.M. regulation of the human to and 2002; in adipose tissue may increase eNOS expression in obese iNOS expression in adipocytes is increased by as tumor necrosis factor-α and (3Kapur S. Marcotte B. Marette A. Mechanism of adipose tissue iNOS induction in endotoxemia.Am. J. Physiol. 1999; 276: E635-E641Google Scholar, 5Ribiere C. Jaubert A.M. Gaudiot N. Sabourault D. Marcus M.L. Boucher J.L. Denis-Henriot D. Giudicelli Y. White adipose tissue nitric oxide synthase: a potential source for NO production.Biochem. Biophys. Res. Commun. 1996; 222: 706-712Google Scholar, 16Pilon G. Penfornis P. Marette A. Nitric oxide production by adipocytes: a role in the pathogenesis of insulin resistance?.Horm. Metab. Res. 2000; 32: 480-484Google Scholar), and increased tissue and levels of are of the S. M. K. F. J. M. Luft F.C. Sharma A.M. between and of in obese 2003; Scholar, and 2003; Scholar). and increased NO formation in adipose tissue of obese be the role of increased adipose tissue NO production in the NO appears to by insulin-stimulated glucose uptake and by and lipolysis (4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 10Jordan J. Tank J. Stoffels M. Franke G. Christensen N.J. Luft F.C. Boschmann M. Interaction between β-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism.J. Clin. Endocrinol. Metab. 2001; 86: 2803-2810Google Scholar, 11Boschmann M. Jordan J. Adams F. Christensen N.J. Tank J. Franke G. Stoffels M. Sharma A.M. Luft F.C. Klaus S. Tissue-specific response to interstitial angiotensin II in humans.Hypertension. 2003; 41: 37-41Google Scholar, D. Perreault M. Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.Am. J. Physiol. 1998; 274: E692-E699Google Scholar, 14Gaudiot N. Jaubert A.M. Charbonnier E. Sabourault D. Lacasa D. Giudicelli Y. Ribiere C. Modulation of white adipose tissue lipolysis by nitric oxide.J. Biol. Chem. 1998; 273: 13475-13481Google Scholar, 15Klatt P. Cacho J. Crespo M.D. Herrera E. Ramos P. Nitric oxide inhibits isoproterenol-stimulated adipocyte lipolysis through oxidative inactivation of the beta-agonist.Biochem. J. 2000; 351: 485-493Google Scholar). increased NO production in adipose tissue of obese may contribute to as described for subcutaneous adipose tissue depots of obese P. lipolysis in J. 1999; Scholar). The effects of NO formation on insulin-stimulated glucose uptake (13Roy D. Perreault M. Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.Am. J. Physiol. 1998; 274: E692-E699Google are most by insulin-stimulated NO production in endothelial NO may in glucose and adipose by tissue blood flow G. Penfornis P. Marette A. Nitric oxide production by adipocytes: a role in the pathogenesis of insulin resistance?.Horm. Metab. Res. 2000; 32: 480-484Google Scholar), and eNOS in the as these are to insulin at the level of the and tissues Y. with of both endothelial and neuronal nitric oxide synthase insulin 2000; Scholar). for the role of NO levels in skeletal and adipose tissue for the of glucose on endothelial insulin receptor D. J. T. K. S. M. The role of endothelial insulin in the regulation of and insulin Clin. 2003; Scholar). NO production by endothelial cells glucose a however, a in insulin was that may be by in tissue blood flow these In however, effects on adipose tissue blood flow been by in vivo NO synthase inhibition (4Andersson K. Gaudiot N. Ribiere C. Elizalde M. Giudicelli Y. Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.Br. J. Pharmacol. 1999; 126: 1639-1645Google Scholar, 10Jordan J. Tank J. Stoffels M. Franke G. Christensen N.J. Luft F.C. Boschmann M. Interaction between β-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism.J. Clin. Endocrinol. Metab. 2001; 86: 2803-2810Google Scholar, 11Boschmann M. Jordan J. Adams F. Christensen N.J. Tank J. Franke G. Stoffels M. Sharma A.M. Luft F.C. Klaus S. Tissue-specific response to interstitial angiotensin II in humans.Hypertension. 2003; 41: 37-41Google Scholar). In vitro that of NO by iNOS stimulation inhibited insulin-stimulated glucose uptake in cells not in mouse G. Penfornis P. Marette A. Nitric oxide production by adipocytes: a role in the pathogenesis of insulin resistance?.Horm. Metab. Res. 2000; 32: 480-484Google Scholar). effects of NO on glucose uptake to be as well as the that NO may act in by influencing blood flow in A role for iNOS has been in of the iNOS in to a with increased insulin and to the of insulin in skeletal M. Marette A. of inducible nitric oxide synthase insulin in 2001; Scholar). inhibited iNOS activity and insulin in and adipose tissue G. P. Marette A. of inducible synthase by of protein a mechanism of of Biol. Chem. Scholar). the the role of NO for regulation in formation of NO by eNOS is important for levels of insulin whereas the of iNOS of iNOS may be to a of insulin In however, the of iNOS and eNOS is not as as in at not in adipose of the of that increased NO production in obese may insulin-stimulated glucose uptake contribute at to in subcutaneous adipose may contribute to increased however, of was by the The and for with the and of The the of and in and expression and with the NO

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