Transgenic and Recombinant Resistin Impair Skeletal Muscle Glucose Metabolism in the Spontaneously Hypertensive Rat

Abstract

Increased serum levels of resistin, a molecule secreted by fat cells, have been proposed as a possible mechanistic link between obesity and insulin resistance. To further investigate the effects of resistin on glucose metabolism, we derived a novel transgenic strain of spontaneously hypertensive rats expressing the mouse resistin gene under the control of the fat-specific aP2 promoter and also performed in vitro studies of the effects of recombinant resistin on glucose metabolism in isolated skeletal muscle. Expression of the resistin transgene was detected by Northern blot analysis in adipose tissue and by real-time PCR in skeletal muscle and was associated with increased serum fatty acids and muscle triglycerides, impaired skeletal muscle glucose metabolism, and glucose intolerance in the absence of any changes in serum resistin concentrations. In skeletal muscle isolated from non-transgenic spontaneously hypertensive rats, in vitro incubation with recombinant resistin significantly inhibited insulin-stimulated glycogenesis and reduced glucose oxidation. These findings raise the possibility that autocrine effects of resistin in adipocytes, leading to release of other prodiabetic effector molecules from fat and/or paracrine actions of resistin secreted by adipocytes embedded within skeletal muscle, may contribute to the pathogenesis of disordered skeletal muscle glucose metabolism and impaired glucose tolerance. Increased serum levels of resistin, a molecule secreted by fat cells, have been proposed as a possible mechanistic link between obesity and insulin resistance. To further investigate the effects of resistin on glucose metabolism, we derived a novel transgenic strain of spontaneously hypertensive rats expressing the mouse resistin gene under the control of the fat-specific aP2 promoter and also performed in vitro studies of the effects of recombinant resistin on glucose metabolism in isolated skeletal muscle. Expression of the resistin transgene was detected by Northern blot analysis in adipose tissue and by real-time PCR in skeletal muscle and was associated with increased serum fatty acids and muscle triglycerides, impaired skeletal muscle glucose metabolism, and glucose intolerance in the absence of any changes in serum resistin concentrations. In skeletal muscle isolated from non-transgenic spontaneously hypertensive rats, in vitro incubation with recombinant resistin significantly inhibited insulin-stimulated glycogenesis and reduced glucose oxidation. These findings raise the possibility that autocrine effects of resistin in adipocytes, leading to release of other prodiabetic effector molecules from fat and/or paracrine actions of resistin secreted by adipocytes embedded within skeletal muscle, may contribute to the pathogenesis of disordered skeletal muscle glucose metabolism and impaired glucose tolerance. In industrialized societies, type 2 diabetes is a common cause of morbidity and mortality that is characterized by insulin resistance often in association with central obesity. However, the mechanisms that underlie the widely recognized relationship between obesity and insulin resistance remain to be defined. Although skeletal muscles are quantitatively the most important site of insulin-stimulated glucose disposal (1DeFronzo D.J. Bonadonna R.C. Ferrannini E. Diabetes Care. 1992; 15: 318-368Crossref PubMed Scopus (1897) Google Scholar), adipose tissue clearly exerts a major influence on carbohydrate metabolism because changes in body fat mass can have substantial effects on insulin action and glucose tolerance. Moreover, recent studies demonstrating that adipose tissue can secrete a number of molecules that modulate carbohydrate and lipid metabolism strongly suggest that body fat is more than just a passive reservoir for fuel in the form of triglycerides. Recently, a new hormone produced by fat cells and termed resistin was discovered that could represent an important link between obesity and insulin-resistant diabetes (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar, 3Holcomb I.N. Kabakoff R.C. Chan B. Baker T.W. Gurney A. Henzel W. Nelson C. Lowman H.B. Wright B.D. Skelton N.J. Frantz G.D. Tumas D.B. Peale Jr., F.V. Shelton D.L. Hebert C.C. EMBO J. 2000; 19: 4046-4055Crossref PubMed Scopus (600) Google Scholar, 4Kim K.H. Lee K. Moon Y.S. Sul H.S. J. Biol. Chem. 2001; 276: 11252-11256Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). Resistin is a cysteine-rich polypeptide expressed primarily in white adipose tissue that is induced during 3T3-L1 adipogenesis and may also serve as a feedback regulator to inhibit adipocyte generation (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar, 3Holcomb I.N. Kabakoff R.C. Chan B. Baker T.W. Gurney A. Henzel W. Nelson C. Lowman H.B. Wright B.D. Skelton N.J. Frantz G.D. Tumas D.B. Peale Jr., F.V. Shelton D.L. Hebert C.C. EMBO J. 2000; 19: 4046-4055Crossref PubMed Scopus (600) Google Scholar, 4Kim K.H. Lee K. Moon Y.S. Sul H.S. J. Biol. Chem. 2001; 276: 11252-11256Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). Message and protein levels of resistin are decreased by fasting and increased by refeeding, possibly in response to changes in insulin levels (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar, 4Kim K.H. Lee K. Moon Y.S. Sul H.S. J. Biol. Chem. 2001; 276: 11252-11256Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). Moreover, Steppan et al. (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar) have found that treatment of mice with recombinant resistin can impair glucose tolerance and that administration of anti-resistin antibody improves blood glucose and insulin action in mice with diet-induced obesity (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar). Incubation of 3T3-L1 adipocytes with recombinant resistin has also been reported to inhibit insulin-stimulated glucose uptake (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar). In addition, resistin mRNA levels can be suppressed by exposure to either fatty acids or ligands for the peroxisome proliferator-activated receptor γ (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar). However, in various rodent models of obesity, conflicting results have been reported regarding the effects of systemically administered peroxisome proliferator-activated receptor γ ligands on resistin expression, perhaps because of the fact that these ligands can influence a host of factors that may differentially regulate resistin (5Banerjee R.R. Lazar M.A. J. Mol. Med. 2003; 81: 218-226Crossref PubMed Scopus (125) Google Scholar, 6Juan C.C. Au L.C. Fang V.S. Kang S.F. Ko Y.H. Kuo S.F. Hsu Y.P. Kwok C.F. Ho L.T. Biochem. Biophys. Res. Commun. 2001; 289: 1328-1333Crossref PubMed Scopus (114) Google Scholar, 7Moore G.B.T. Chapman H. Holder J.C. Lister C.A. Piercy V. Smith S.A. Clapham J.C. Biochem. Biophys. Res. Commun. 2001; 286: 735-741Crossref PubMed Scopus (141) Google Scholar, 8Way J.M. Gorgun C.Z. Tong Q. Uysal K.T. Brown K.K. Harrington W.W. Oliver Jr., W.R. Willson T.M. Kliewer S.A. Hotamisligil G.S. J. Biol. Chem. 2001; 27: 25651-25653Abstract Full Text Full Text PDF Scopus (406) Google Scholar). Based on measurements of resistin expression in fat tissue in humans and in animals with type 2 diabetes and or obesity, a number of investigators have recently raised questions regarding the potential relevance of resistin to the pathogenesis of insulin resistance. For example, whereas some investigators have found evidence of resistin expression in samples of human subcutaneous and abdominal fat (9McTernan C.L. McTernan P.G. Harte A.L. Levick P.L. Barnett A.H. Kumar S. Lancet. 2002; 359: 46-47Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 10Savage D.B. Sewter C.P. Klenk E.S. Segal D.G. Vidal-Puig A. Considine R.V. O'Rahilly S. Diabetes. 2001; 50: 2199-2202Crossref PubMed Scopus (704) Google Scholar), others have found it difficult to detect mRNA for resistin in either adipocytes or subcutaneous adipose tissue isolated from insulin-resistant subjects (11Nagaev I. Smith U. Biochem. Biophys. Res. Commun. 2001; 285: 561-564Crossref PubMed Scopus (370) Google Scholar). Expression of resistin in white adipose tissue has also been reported to be significantly decreased in several animal models of obesity-associated insulin resistance (6Juan C.C. Au L.C. Fang V.S. Kang S.F. Ko Y.H. Kuo S.F. Hsu Y.P. Kwok C.F. Ho L.T. Biochem. Biophys. Res. Commun. 2001; 289: 1328-1333Crossref PubMed Scopus (114) Google Scholar, 12Fukui Y. Motojima K. Diabetes Obes. Metab. 2002; 4: 342-345Crossref PubMed Scopus (53) Google Scholar, 13Fujita H. Fujishima H. Morii T. Koshimura J. Narita T. Kakei M. Ito S. Biochem. Biophys. Res. Commun. 2002; 298: 345-349Crossref PubMed Scopus (54) Google Scholar). However, the lack of correlation between resistin mRNA levels in isolated adipocytes and insulin resistance does not exclude the possibility that resistin may be contributing to the pathogenesis of disordered carbohydrate metabolism in either liver or skeletal muscle. In Sprague-Dawley rats, intra-arterial infusion of recombinant resistin over a period of 5 h has recently been reported to promote glucose intolerance by impairing insulin action on hepatic glucose metabolism (14Rajala M.W. Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; 111: 225-230Crossref PubMed Scopus (485) Google Scholar). This observation raises the possibility that local of molecules the a in the pathogenesis of type 2 is also that paracrine effects of resistin produced by adipocytes embedded within skeletal muscle contribute to the pathogenesis of impaired glucose tolerance in the absence of changes in either levels of resistin or resistin expression in or subcutaneous However, studies have been performed to investigate the effects of resistin on skeletal muscle glucose metabolism or the relationship between levels of resistin and glucose tolerance. In we the effects of resistin on glucose metabolism in the spontaneously hypertensive spontaneously hypertensive fatty glucose tolerance a widely animal of the that is to insulin resistance in to a in the fatty M. V. M. V. K. M. B. L. R.C. Y. J. T.W. J. Clin. Invest. PubMed Scopus Google Scholar, C.A. C.C. E. T.W. V. M. A. J. PubMed Scopus Google Scholar, M. V. V. A. V. L. A. J. T.W. 2001; 27: PubMed Scopus Google Scholar). have found that transgenic expression of the mouse resistin gene under the control of the aP2 promoter in the and increased muscle triglycerides, and glucose disposal in skeletal muscle, and glucose intolerance in the absence of changes in levels of resistin or In addition, we that recombinant resistin can inhibit glucose and insulin-stimulated glycogenesis in isolated muscle from non-transgenic These findings raise the possibility that paracrine actions of resistin secreted by adipocytes embedded within skeletal muscle or autocrine effects of resistin in adipocytes leading to the release of other prodiabetic effector molecules from fat or may contribute to the pathogenesis of disordered skeletal muscle glucose metabolism and impaired glucose tolerance. resistin transgene was expressed on the of the strain M. V. M. V. K. M. B. L. R.C. Y. J. T.W. J. Clin. Invest. PubMed Scopus Google Scholar, C.A. C.C. E. T.W. V. M. A. J. PubMed Scopus Google Scholar, M. V. V. A. V. L. A. J. T.W. 2001; 27: PubMed Scopus Google Scholar). rats in an animal and to and in control and the rats a with from the of for of the performed in with the of the and by the of the of of derived by of with a mouse resistin that was by PCR of from fat tissue of a Resistin to the resistin (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar). in to of the mouse resistin a hormone and the fat-specific aP2 promoter by of of recombinant or of to et al. B. S. L. I. Scholar). rats detected by PCR for the mouse resistin and of the new strain is as the Expression of blot analysis was to expression of the mouse resistin transgene and resistin gene in adipose for Northern analysis was by of the of the mouse resistin gene and from the transgene PCR analysis was to for possible expression of the mouse resistin transgene in skeletal muscle. gene was as an control with expression of the mouse resistin transgene to in the of et al. H. 2002; Google Scholar, H. 2002; Scholar). was by of muscle mRNA by real-time PCR on an and and from 2 of tissue was with of and of for for on samples for by and for the samples for was as a protein For the protein with 2 of to from and to for 5 on and and the was V. of samples was For a protein was with and for h was in for Resistin protein was detected with a resistin antibody This antibody does not between mouse and antibody was as a and in incubation with the antibody was and with the for h was with the and the was detected the analysis and by glucose tolerance performed a glucose of body h of was from the the glucose and and and and glucose in isolated muscle by the of and as A. L. 27: Full Text PDF PubMed Scopus Google Scholar, L. V. V. V. E. M. T.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). muscles to a in in by and from other muscles and and for 2 h in that and serum with or a of was central of the incubation and of was the to for and the was quantitatively the of for of For of insulin-stimulated of glucose was and glucose was as A. L. 27: Full Text PDF PubMed Scopus Google Scholar, L. V. V. V. E. M. T.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of in liver and muscle, under and for h in was and the was was and under was in and was by of Resistin on and in from the and glucose as in muscles isolated from resistin was to incubation a of glucose levels by the glucose blood and fatty levels an by insulin a insulin levels of a from resistin with an that with mouse and resistin of the are expressed as between control and by or as was as Expression of and by derived from of a with In the fat from the Northern blot analysis the expression of the mouse resistin transgene and the resistin gene expression of the resistin the of the and that are of resistin in the and in a These are in to reported for the is to resistin whereas the mouse resistin K.H. Lee K. Moon Y.S. Sul H.S. J. Biol. Chem. 2001; 276: 11252-11256Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). In the a for the mouse resistin transgene could be detected in that is in from the resistin and that is than the type mouse resistin because of In to mRNA for the mouse resistin transgene by Northern blot analysis in fat from the transgenic we to detect skeletal muscle expression of the mouse resistin transgene to that of by real-time PCR expression of the mouse resistin gene in fat or muscle by either Northern blot analysis or real-time blot analysis of adipose tissue expression of resistin protein in the rats than in of Resistin on and the of between rats and with to either body or fat resistin levels between rats and as by an that with mouse and resistin of insulin and glucose in rats, and to in and 2 In rats, serum levels of also not with in transgene In serum of significantly increased in transgenic animals with Increased serum levels also in the rats during the glucose tolerance In the rats, the increased serum levels associated with increased muscle whereas in hepatic between the rats and the fat and serum resistin fat body in a new of Resistin on rats impaired glucose tolerance with the under the glucose tolerance significantly in the than in the h and These results are with the studies of Steppan et al. (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar) in administration of recombinant resistin was found to impair glucose tolerance in However, in to the studies of Steppan et al. (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar) in impaired glucose tolerance induced by of recombinant resistin was associated with increased serum levels of resistin, the studies that transgenic expression of mouse resistin on the can impair glucose tolerance in the absence of changes in of Resistin on muscle isolated from transgenic expressing the mouse resistin glycogenesis and glucose significantly reduced in the and absence of insulin a and and glucose metabolism impaired in skeletal muscle of transgenic rats with These findings are in with the recent studies of Moon et al. B. J. 2003; 285: PubMed Scopus Google Scholar) in recombinant resistin was found to inhibit glucose uptake in skeletal muscle cells in the and absence of However, in the studies of Moon et al. B. J. 2003; 285: PubMed Scopus Google Scholar), the effects of recombinant resistin on of glucose disposal not and the to the effects of recombinant resistin on glucose metabolism in cells in skeletal muscle tissue is findings that transgenic expression of resistin can impair of the that skeletal muscle glucose disposal in isolated tissue that has not been to increased levels of resistin in or to recombinant resistin in of Resistin on of isolated muscle from non-transgenic with recombinant resistin significantly impaired insulin glycogenesis muscle glycogenesis was significantly in the of recombinant resistin insulin than in the of insulin Although recombinant resistin also a to glycogenesis in the absence of the not Incubation of muscle from non-transgenic with recombinant resistin significantly reduced glucose and a in glucose in the of insulin These findings in muscle with recombinant resistin to the results in muscle isolated from transgenic that the mouse aP2 resistin of resistin in the potential of molecules in the pathogenesis of insulin resistance and type 2 a number of have been that to raise regarding the possibility of an important relationship between resistin and various that are of obesity and type 2 For example, some investigators have that in or correlation between resistin mRNA levels in adipose tissue or adipocytes and insulin or body mass D.B. Sewter C.P. Klenk E.S. Segal D.G. Vidal-Puig A. Considine R.V. O'Rahilly S. Diabetes. 2001; 50: 2199-2202Crossref PubMed Scopus (704) Google Scholar, I. Smith U. Biochem. Biophys. Res. Commun. 2001; 285: 561-564Crossref PubMed Scopus (370) Google Scholar, J. S. K. Obes. Res. 2002; PubMed Scopus Google Scholar). In a of animal models of obesity that are associated with insulin expression of resistin in white adipose tissue has also been reported to be significantly decreased (6Juan C.C. Au L.C. Fang V.S. Kang S.F. Ko Y.H. Kuo S.F. Hsu Y.P. Kwok C.F. Ho L.T. Biochem. Biophys. Res. Commun. 2001; 289: 1328-1333Crossref PubMed Scopus (114) Google Scholar, 12Fukui Y. Motojima K. Diabetes Obes. Metab. 2002; 4: 342-345Crossref PubMed Scopus (53) Google Scholar, 13Fujita H. Fujishima H. Morii T. Koshimura J. Narita T. Kakei M. Ito S. Biochem. Biophys. Res. Commun. 2002; 298: 345-349Crossref PubMed Scopus (54) Google Scholar), some investigators to that to be to than cause insulin resistance in and to suggest that of the resistin is not in H. Fujishima H. Morii T. Koshimura J. Narita T. Kakei M. Ito S. Biochem. Biophys. Res. Commun. 2002; 298: 345-349Crossref PubMed Scopus (54) Google Scholar). However, the of to insulin resistance and type 2 the often relationship between mRNA levels and protein levels as as the lack of regarding potential feedback between insulin resistance and resistin expression, it is to a potential for resistin in the pathogenesis of insulin resistance in either humans or in animals G.S. J. Clin. Invest. 2003; 111: PubMed Scopus Google Scholar). In the we have found that transgenic expression of mouse resistin under control of the aP2 promoter on the of the in serum and skeletal muscle lipid and glucose disposal in skeletal muscle, and glucose intolerance in the absence of changes in levels of resistin, or results with transgenic expression of mouse resistin under the control of a L. V. V. J. and T. W. the findings are to the effects of transgenic expression of resistin than the effects of transgenic expression the aP2 In addition, we that recombinant resistin can glucose and inhibit insulin-stimulated glycogenesis in isolated muscle from non-transgenic These findings are with the studies of Steppan et al. (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar) in of recombinant resistin was found to impair glucose tolerance in mice and suggest under the and of the resistin may contribute to impaired glucose tolerance by of effects on skeletal muscle glucose Although the studies have on the effects of resistin on skeletal muscle glucose metabolism, not be to that the glucose intolerance in the strain is or a of skeletal muscle insulin resistance. In a of the insulin in Sprague-Dawley rats, et al. (14Rajala M.W. Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; 111: 225-230Crossref PubMed Scopus (485) Google Scholar) recently found that intra-arterial infusion of recombinant resistin over a period of 5 h can impair insulin action on hepatic glucose investigators have reported that recombinant resistin can inhibit insulin-stimulated glucose uptake in 3T3-L1 adipocytes and in skeletal muscle cells (2Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3974) Google Scholar, B. J. 2003; 285: PubMed Scopus Google Scholar). These with the findings in isolated skeletal muscle from transgenic and non-transgenic rats, suggest that resistin may contribute to the pathogenesis of insulin resistance effects on of these effects of resistin in also on the and under are In the of et al. (14Rajala M.W. Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; 111: 225-230Crossref PubMed Scopus (485) Google Scholar) in Sprague-Dawley rats, the intra-arterial infusion of recombinant resistin impaired hepatic significantly glucose However, of recombinant resistin may not the effects of resistin in and not have the potential to autocrine or paracrine effects of resistin that may of changes in levels of the studies of et al. (14Rajala M.W. Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; 111: 225-230Crossref PubMed Scopus (485) Google Scholar), it is possible that exposure of skeletal muscle to resistin from the or to resistin that is secreted by adipocytes embedded within muscle tissue may impair skeletal muscle glucose In addition, of resistin to skeletal muscle glucose metabolism in Sprague-Dawley rats under the of et al. (14Rajala M.W. Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; 111: 225-230Crossref PubMed Scopus (485) Google Scholar), it is possible that or exposure to resistin influence skeletal muscle glucose disposal in Sprague-Dawley rats under other or or in other that are to insulin resistance. In the the results of that exposure to resistin in as as exposure to resistin in vitro can impair skeletal muscle glucose metabolism in a animal of the M. V. M. V. K. M. B. L. R.C. Y. J. T.W. J. Clin. Invest. PubMed Scopus Google Scholar, Ho H. Metab. Res. PubMed Scopus Google Scholar, J. Med. Full Text PDF PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar). the with the of the effects of increased levels of resistin and to in glucose metabolism in the absence of changes in levels of that measurements of serum resistin levels of resistin the and the findings suggest that resistin may be skeletal muscle glucose paracrine or autocrine mechanisms or Moreover, serum resistin levels been found to be increased in the transgenic the observation of impaired glucose metabolism in isolated skeletal muscle in the absence of resistin in the be findings could the of some type of in exposure to resistin in is to impair skeletal muscle glucose metabolism in the absence of resistin in Although we could not detect any in levels of resistin, or between and non-transgenic we significantly increased lipid levels in the serum and skeletal muscle of the transgenic In of the relationship between skeletal muscle insulin resistance and increased serum and skeletal muscle Clin. Metab. Care. 2002; PubMed Scopus Google Scholar, J.M. 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PubMed Scopus Google Scholar). observation of impaired glucose metabolism in skeletal muscle isolated from transgenic that expression of the mouse resistin transgene as as in skeletal muscle from non-transgenic that was to recombinant resistin in vitro further These findings raise the possibility that paracrine effects of resistin from adipocytes embedded in skeletal muscle also be contributing to in skeletal muscle glucose This be of recent studies demonstrating a correlation between insulin resistance and the of adipose tissue the of skeletal muscle in the Diabetes Care. 2001; PubMed Scopus Google Scholar). In it may be of to investigate the effects of resistin that are expressed under the control of other as the for muscle In in the we have found that transgenic expression of the mouse resistin gene under control of the aP2 promoter can impair glucose tolerance and inhibit and glucose metabolism in skeletal muscle in the absence of increased levels of These findings raise the possibility that resistin may promote glucose intolerance mechanisms that not on changes in levels of resistin and that could autocrine effects of resistin in paracrine effects of resistin in skeletal muscle, or of the of or tissue levels of resistin or of effector molecules to insulin the findings studies of the effects of resistin on lipid metabolism and skeletal muscle glucose metabolism under a of other and