Effects of resistin on skeletal glucose metabolism

Abstract

Resistin is an adipokine highly related to insulin resistance (IR). The purpose of our research was to investigate how resistin influences skeletal glucose metabolism and explore its mechanisms. We constructed the recombinant plasmid pcDNA3.1 expressing resistin and then transfected it into C2C12 myocytes. The expression of resistin in C2C12 myocytes was detected by Western blotting. Glucose uptake was measured by ³H labeled glucose; glucose oxidation and glycogen synthesis was detected with ¹⁴C-labeled glucose. GLUT4 mRNA was measured by reverse transcription polymerase chain reaction (RT-PCR). We observed that resistin was expressed in transfected myocytes, and resistin decreased insulin induced glucose uptake rate by 28%–31% and inhibited the expression of GLUT4 mRNA. However, there was no significant difference in basal glucose uptake, and glucose oxidation and glycogen synthesis remained unchanged in all groups. It is concluded that resistin inhibits insulin induced glucose uptake in myocytes by downregulating the expression of GLUT4 and it has no effects on glucose oxidation and glycogen synthesis. Our findings may provide a clue to understand the roles of resistin in the pathogenesis of skeletal IR.

Keywords

resistin / insulin resistance / skeletal muscle

References

[1] SteppanC M, BaileyS T, BhatS, BrownE J, BanerjeeR R, WrightC M, PatelH R, AhimaR S, LazarM A. The hormone resistin links obesity to diabetes. Nature, 2001, 409(6818): 307–312

[2] PetersenK F, DufourS, SavageD B, BilzS, SolomonG, YonemitsuS, ClineG W, BefroyD, ZemanyL, KahnB B, PapademetrisX, RothmanD L, ShulmanG I. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A, 2007, 104(31): 12587–12594

[3] HausdorffS F, FingarD C, MoriokaK, GarzaL A, WhitemanE L, SummersS A, BirnbaumM J. Identification of wortmannin sensitive targets in 3T3–L1adipocytes. J Biol Chem, 1999, 274(35): 24677–24684

[4] LassarA B, SkapekS X, NovitchB, LassarA B, SkapekS K, NovitchB. Regulatory mechanisms that coordinate skeletal muscle differentiation and cell cycle withdrawal. Curr Opin Cell Biol, 1994, 6(6): 788–794

[5] MoonB, KwanJ J, DuddyN, SweeneyG, BegumN. Resistin inhibits glucose uptake in L6 skeletal muscle cells independent of changes in insulin signaling components and Glut-4 translocation. Am J Physiol Endocrinol Metab, 2003, 285(1): E106–E115

[6] FanH Q, GuN, LiuF, FeiL, PanX Q, GuoM, ChenR H, GuoX R. Prolonged exposure to resistin inhibits glucose uptake in rat skeletal muscles. Acta Pharmacol Sin, 2007, 28(3): 410–416

[7] PalanivelR, MaidaA, LiuY, SweeneyG. Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia, 2006, 49(1): 183–190

[8] PravenecM, KazdováL, LandaV, ZidekV, MlejnekP, JansaP, WangJ, QiN, KurtzT W. Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat. J Biol Chem, 2003, 278(46): 45209–45215

[9] DietzeD, KoenenM, RöhrigK, HorikoshiH, HaunerH, EckelJ. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes, 2002, 51(8): 2369–2376

[10] SavageD B, SewterC P, KlenkE S, SegalD G, Vidal-PuigA, ConsidineR V, O’RahillyS. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes, 2001, 50(10): 2199–2202

[11] PatelL, BuckelsA C, KinghornI J, MurdockP R, HolbrookJ D, PlumptonC, MacpheeC H, SmithS A. Resistin is expressed in human macrophages and directly regulated by PPAR γ activators. Biochem Biophys Res Commun, 2003, 300(2): 472–476

[12] YangR Z, HuangQ, XuA, McLenithanJ C, EisenJ A, ShuldinerA R, AlkanS, GongD W, EisonJ A. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun, 2003, 310(3): 927–935

[13] QiY, NieZ, LeeY S, SinghalN S, SchererP E, LazarM A, AhimaR S. Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes, 2006, 55(11): 3083–3090

[14] KeZ, ZhouF, WangL, ChenS, LiuF, FanX, TangF, LiuD, ZhaoG. Down-regulation of Wnt signaling could promote bone marrow-derived mesenchymal stem cells to differentiate into hepatocytes. Biochem Biophys Res Commun, 2008, 367(2): 342–348

[15] BanerjeeR R, RangwalaS M, ShapiroJ S, RichA S, RhoadesB, QiY, WangJ, RajalaM W, PocaiA, SchererP E, SteppanC M, AhimaR S, ObiciS, RossettiL, LazarM A. Regulation of fasted blood glucose by resistin. Science, 2004, 303(5661): 1195–1198

[16] MuseE D, ObiciS, BhanotS, MoniaB P, McKayR A, RajalaM W, SchererP E, RossettiL. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest, 2004, 114(2): 232–239

[17] SatohH, NguyenM T, MilesP D, ImamuraT, UsuiI, OlefskyJ M. Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats. J Clin Invest, 2004, 114(2): 224–231

[18] LiF P, HeJ, LiZ Z, LuoZ F, YanL, LiY. Effects of resistin expression on glucose metabolism and hepatic insulin resistance. Endocrine, 2009, 35(2): 243–251

[19] CuratC A, WegnerV, SengenèsC, MiranvilleA, TonusC, BusseR, BouloumiéA. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia, 2006, 49(4): 744–747

[20] AxelssonJ, BergstenA, QureshiA R, HeimbürgerO, BárányP, LönnqvistF, LindholmB, NordforsL, AlvestrandA, StenvinkelP. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int, 2006, 69(3): 596–604

[21] ReillyM P, LehrkeM, WolfeM L, RohatgiA, LazarM A, RaderD J. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation, 2005, 111(7): 932–939

[22] BokarewaM, NagaevI, DahlbergL, SmithU, TarkowskiA. Resistin, an adipokine with potent proinflammatory properties. J Immunol, 2005, 174(9): 5789–5795

[23] SilswalN, SinghA K, ArunaB, MukhopadhyayS, GhoshS, EhteshamN Z. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun, 2005, 334(4): 1092–1101

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