Endocrine Pharmacology

Resistin induces insulin resistance, but does not affect glucose output in rat-derived hepatocytes

Article metrics

Abstract

Aim:

The aim of the present study was to observe the effects of resistin on insulin sensitivity and glucose output in rat-derived hepatocytes.

Methods:

The rat hepatoma cell line H4IIE was cultured and stimulated with resistin; supernant glucose and glycogen content were detected. The insulin receptor substrate (IRS)-1 and IRS-2, protein kinase B/Akt, glycogen synthase kinase-3β (GSK-3β), the suppressor of cytokine signaling 3 (SOCS-3) protein content, as well as the phosphorylation status were assessed by Western blotting. Specific antisense oligodeoxynucleotides directed against SOCS-3 were used to knockdown SOCS-3.

Results:

Resistin induced insulin resistance, but did not affect glucose output in rat hepatoma cell line H4IIE. Resistin attenuated multiple effects of insulin, including insulin-stimulated glycogen synthesis and phosphorylation of IRS, protein kinase B/Akt, as well as GSK-3β. Resistin treatment markedly induced the gene and protein expression of SOCS-3, a known inhibitor of insulin signaling. Furthermore, a specific antisense oligodeoxynucleotide directed against SOCS-3 treatment prevented resistin from antagonizing insulin action.

Conclusion:

The major function of resistin on liver is to induce insulin resistance. SOCS-3 induction may contribute to the resistin-mediated inhibition of insulin signaling in H4IIE hepatocytes.

References

  1. 1

    Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–81.

  2. 2

    Hansen HO, Andreasen PH, Mandrup S, Kristiansen K, Knudsen J . Induction of lipogenesis during differentiation in a “preadipocyte” cell line. J Biol Chem 1976; 251: 6462–4.

  3. 3

    Steppan CM, Lazar MA . Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 2002; 13: 18–23.

  4. 4

    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–12.

  5. 5

    Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, et al. A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA 2001; 98: 502–6.

  6. 6

    Palanivel R, Maida A, Liu Y, Sweeney G . Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia 2006; 49: 183–90.

  7. 7

    Fan HQ, Gu N, Liu F, Fei L, Pan XQ, Guo M, et al. Prolonged exposure to resistin inhibits glucose uptake in rat skeletal muscles. Acta Pharmacol Sin 2007; 28: 410–6.

  8. 8

    Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA . Activation of SOCS-3 by resistin. Mol Cell Biol 2005; 25: 1569–75.

  9. 9

    Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, et al. Regulation of fasted blood glucose by resistin. Science 2004; 303: 1195–8.

  10. 10

    Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 1997; 387: 921–4.

  11. 11

    Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature 1997; 387: 917–21.

  12. 12

    Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, et al. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-α in the adipose tissue of obese mice. J Biol Chem 2001; 276: 47 944–9.

  13. 13

    Rui L, Yuan M, Frantz D, Shoelson S, White MF . SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 2002; 277: 42 394–8.

  14. 14

    Janjic D, Wollheim CB . Islet cell metabolism is reflected by the MTT (tetrazolium) colorimetric assay. Diabetologia 1992; 35: 482–5.

  15. 15

    Chun Y, Yin ZD . Glycogen assay for diagnosis of female genital Chlamydia trachomatis infection. J Clin Microbiol 1998; 36: 1081–2.

  16. 16

    Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, et al. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J Clin Endocrinol Metab 2005; 90: 1055–60.

  17. 17

    Staubs PA, Nelson JG, Reichart DR, Olefsky JM . Platelet-derived growth factor inhibits insulin stimulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase in 3T3-L1 adipocytes without affecting glucose transport. J Biol Chem 1998; 273: 25 139–47.

  18. 18

    Butler M, McKay RA, Popoff IJ, Gaarde WA, Witchell D, Murray SF, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 2002; 51: 1028–34.

  19. 19

    Calegari VC, Bezerra RM, Torsoni MA, Torsoni AS, Franchini KG, Saad MJ, et al. Suppressor of cytokine signaling 3 is induced by angiotensin II in heart and isolated cardiomyocytes, and participates in desensitization. Endocrinology 2003; 144: 4586–96.

  20. 20

    Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF, et al. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes 2003; 52: 2239–48.

  21. 21

    Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, et al. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 2004; 114: 232–9.

  22. 22

    Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, et al. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 1995; 14: 2816–26.

  23. 23

    Zhou L, Li Y, Xia T, Feng S, Chen X, Yang Z . Resistin over expression impaired glucose tolerance in hepatocytes. Eur Cytokine Netw 2006; 17: 189–95.

  24. 24

    Kushiyama A, Shojima N, Ogihara T, Inukai K, Sakoda H, Fujishiro M, et al. Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. J Biol Chem 2005; 280: 42016–25.

  25. 25

    Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, et al. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab 2004; 89: 150–6.

  26. 26

    Rajala MW, Obici S, Scherer PE, Rossetti L . Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest 2003; 111: 225–30.

  27. 27

    Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 2003; 278: 13740–6.

Download references

Author information

Correspondence to Rong-hua Chen or Xi-rong Guo.

Additional information

This study was supported by grants from the National Natural Science Foundation of China (No 30371502 and 30571978), the Natural Science Foundation of Jiangsu Province (No BK2001120), and a grant from Jiangsu Province Health Department (No RC2002061).

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • resistin
  • hepatocytes
  • insulin resistance
  • suppressor of cytokine signaling 3

Further reading