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Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

Nature volume 436, pages 356–362 (2005)Cite this article

Abstract

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4-/-) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4-/- mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived ‘signal’ that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

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Figure 1: Elevation of RBP4 in insulin-resistant mouse models.
Figure 2: Rosiglitazone treatment decreases RBP4 levels in adipose- Glut4 -/- mice.
Figure 3: Elevated serum RBP4 causes insulin resistance.
Figure 4: Lowering serum RBP4 levels improves insulin action.
Figure 5: Effects of RBP4 on insulin signalling, hepatic PEPCK expression and hepatocyte glucose production.

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References

  1. Despres, J. P. et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N. Engl. J. Med. 334, 952–957 (1996)

    Article  CAS  PubMed  Google Scholar 

  2. Shepherd, P. R. & Kahn, B. B. Glucose transporters and insulin action—implications for insulin resistance and diabetes mellitus. N. Engl. J. Med. 341, 248–257 (1999)

    Article  CAS  PubMed  Google Scholar 

  3. DeFronzo, R. A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 5, 171–269 (1997)

    Google Scholar 

  4. Shepherd, P. R. et al. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J. Biol. Chem. 268, 22243–22246 (1993)

    CAS  PubMed  Google Scholar 

  5. Abel, E. D. et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733 (2001)

    Article  CAS  ADS  PubMed  Google Scholar 

  6. Tozzo, E., Gnudi, L. & Kahn, B. B. Amelioration of insulin resistance in streptozotocin diabetic mice by transgenic overexpression of GLUT4 driven by an adipose-specific promoter. Endocrinology 138, 1604–1611 (1997)

    Article  CAS  PubMed  Google Scholar 

  7. Carvalho, E., Kotani, K., Peroni, O. & Kahn, B. B. Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. Am. J. Physiol. Endocrinol. Metab. doi:10.1152/ajpendo.0016.2005 (2005)

  8. Kershaw, E. E. & Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548–2556 (2004)

    Article  CAS  PubMed  Google Scholar 

  9. Quadro, L. et al. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J. 18, 4633–4644 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Minokoshi, Y., Kahn, C. R. & Kahn, B. B. Tissue-specific ablation of the GLUT4 glucose transporter or the insulin receptor challenges assumptions about insulin action and glucose homeostasis. J. Biol. Chem. 278, 33609–33612 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Kitamura, T., Kahn, C. R. & Accili, D. Insulin receptor knockout mice. Annu. Rev. Physiol. 65, 313–332 (2003)

    Article  CAS  PubMed  Google Scholar 

  12. Blaner, W. S. Retinol-binding protein: the serum transport protein for vitamin A. Endocr. Rev. 10, 308–316 (1989)

    Article  CAS  PubMed  Google Scholar 

  13. Kotani, K., Peroni, O. D., Minokoshi, Y., Boss, O. & Kahn, B. B. GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J. Clin. Invest. 114, 1666–1675 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Masuzaki, H. et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 294, 2166–2170 (2001)

    Article  CAS  ADS  PubMed  Google Scholar 

  15. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004)

    Article  CAS  ADS  PubMed  Google Scholar 

  16. Nikoulina, S. E. et al. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49, 263–271 (2000)

    Article  CAS  PubMed  Google Scholar 

  17. Lee, C. H., Olson, P. & Evans, R. M. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144, 2201–2207 (2003)

    Article  CAS  PubMed  Google Scholar 

  18. Kotani, K., Kim, Y. B., Peroni, O., Mundt, A. & Kahn, B. B. Rosiglitazone treatment normalizes glucose tolerance in adipose-specific GLUT4 knockout mice but renders muscle-specific GLUT4 knockout more diabetic [abstract]. Diabetes 50, A274 (2001)

    Google Scholar 

  19. Quadro, L. et al. Muscle expression of human retinol-binding protein (RBP). Suppression of the visual defect of RBP knockout mice. J. Biol. Chem. 277, 30191–30197 (2002)

    Article  CAS  PubMed  Google Scholar 

  20. Naylor, H. M. & Newcomer, M. E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 38, 2647–2653 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Kato, M., Kato, K., Blaner, W. S., Chertow, B. S. & Goodman, D. S. Plasma and cellular retinoid-binding proteins and transthyretin (prealbumin) are all localized in the islets of Langerhans in the rat. Proc. Natl Acad. Sci. USA 82, 2488–2492 (1985)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  22. Malpeli, G., Folli, C. & Berni, R. Retinoid binding to retinol-binding protein and the interference with the interaction with transthyretin. Biochim. Biophys. Acta 1294, 48–54 (1996)

    Article  PubMed  Google Scholar 

  23. Mothe, I. & Van Obberghen, E. Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. J. Biol. Chem. 271, 11222–11227 (1996)

    Article  CAS  PubMed  Google Scholar 

  24. Anai, M. et al. Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. Diabetes 48, 158–169 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Pagliassotti, M. J., Kang, J., Thresher, J. S., Sung, C. K. & Bizeau, M. E. Elevated basal PI 3-kinase activity and reduced insulin signalling in sucrose-induced hepatic insulin resistance. Am. J. Physiol. Endocrinol. Metab. 282, E170–E176 (2002)

    Article  CAS  PubMed  Google Scholar 

  26. Shin, D. J., Odom, D. P., Scribner, K. B., Ghoshal, S. & McGrane, M. M. Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver. Mol. Cell. Endocrinol. 195, 39–54 (2002)

    Article  CAS  PubMed  Google Scholar 

  27. Kahn, C. R., Lauris, V., Koch, S., Crettaz, M. & Granner, D. K. Acute and chronic regulation of phosphoenolpyruvate carboxykinase mRNA by insulin and glucose. Mol. Endocrinol. 3, 840–845 (1989)

    Article  CAS  PubMed  Google Scholar 

  28. Wang, J. C., Stafford, J. M., Scott, D. K., Sutherland, C. & Granner, D. K. The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis. J. Biol. Chem. 275, 14717–14721 (2000)

    Article  CAS  PubMed  Google Scholar 

  29. Basualdo, C. G., Wein, E. E. & Basu, T. K. Vitamin A (retinol) status of First Nation adults with non-insulin-dependent diabetes mellitus. J. Am. Coll. Nutr. 16, 39–45 (1997)

    Article  CAS  PubMed  Google Scholar 

  30. Abahusain, M. A., Wright, J., Dickerson, J. W. & de Vol, E. B. Retinol, alpha-tocopherol and carotenoids in diabetes. Eur. J. Clin. Nutr. 53, 630–635 (1999)

    Article  CAS  PubMed  Google Scholar 

  31. Meigs, J. B., Panhuysen, C. I., Myers, R. H., Wilson, P. W. & Cupples, L. A. A genome-wide scan for loci linked to plasma levels of glucose and HbA1c in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study. Diabetes 51, 833–840 (2002)

    Article  CAS  PubMed  Google Scholar 

  32. Duggirala, R. et al. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am. J. Hum. Genet. 64, 1127–1140 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tsutsumi, C. et al. Retinoids and retinoid-binding protein expression in rat adipocytes. J. Biol. Chem. 267, 1805–1810 (1992)

    CAS  PubMed  Google Scholar 

  34. Zovich, D. C. et al. Differentiation-dependent expression of retinoid-binding proteins in BFC-1β adipocytes. J. Biol. Chem. 267, 13884–13889 (1992)

    CAS  PubMed  Google Scholar 

  35. Pedersen, O., Kahn, C. R. & Kahn, B. B. Divergent regulation of the Glut 1 and Glut 4 glucose transporters in isolated adipocytes from Zucker rats. J. Clin. Invest. 89, 1964–1973 (1992)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954 (1996)

    Article  CAS  PubMed  Google Scholar 

  37. Koistinen, H. A. et al. Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid. Diabetes Metab. Res. Rev. 17, 391–395 (2001)

    Article  CAS  PubMed  Google Scholar 

  38. Rodondi, N. et al. High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study. Ann. Intern. Med. 136, 582–589 (2002)

    Article  CAS  PubMed  Google Scholar 

  39. Kliewer, S. A., Xu, H. E., Lambert, M. H. & Willson, T. M. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog. Horm. Res. 56, 239–263 (2001)

    Article  CAS  PubMed  Google Scholar 

  40. Sivaprasadarao, A. & Findlay, J. B. The interaction of retinol-binding protein with its plasma-membrane receptor. Biochem. J. 255, 561–569 (1988)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Matarese, V. & Lodish, H. F. Specific uptake of retinol-binding protein by variant F9 cell lines. J. Biol. Chem. 268, 18859–18865 (1993)

    CAS  PubMed  Google Scholar 

  42. Christensen, E. I. et al. Evidence for an essential role of megalin in transepithelial transport of retinol. J. Am. Soc. Nephrol. 10, 685–695 (1999)

    CAS  PubMed  Google Scholar 

  43. Berni, R., Clerici, M., Malpeli, G., Cleris, L. & Formelli, F. Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol. FASEB J. 7, 1179–1184 (1993)

    Article  CAS  PubMed  Google Scholar 

  44. Monaco, H. L. The transthyretin-retinol-binding protein complex. Biochim. Biophys. Acta 1482, 65–72 (2000)

    Article  CAS  PubMed  Google Scholar 

  45. Sheikh, M. S. et al. N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis 16, 2477–2486 (1995)

    Article  CAS  PubMed  Google Scholar 

  46. Um, S. J. et al. Antiproliferative mechanism of retinoid derivatives in ovarian cancer cells. Cancer Lett. 174, 127–134 (2001)

    Article  CAS  PubMed  Google Scholar 

  47. Shen, Q., Cline, G. W., Shulman, G. I., Leibowitz, M. D. & Davies, P. J. Effects of rexinoids on glucose transport and insulin-mediated signalling in skeletal muscles of diabetic (db/db) mice. J. Biol. Chem. 279, 19721–19731 (2004)

    Article  CAS  PubMed  Google Scholar 

  48. Subcommittee on Laboratory Animal Nutrition, Committee on Animal Nutrition, Board on Agriculture, National Research Council. Nutrient Requirements of Laboratory Animals 4th revised edn, 92 (National Academies Press, Washington DC, 1995)

    Google Scholar 

  49. Wang, T. T., Lewis, K. C. & Phang, J. M. Production of human plasma retinol-binding protein in Escherichia coli. Gene 133, 291–294 (1993)

    Article  CAS  PubMed  Google Scholar 

  50. Xie, Y., Lashuel, H. A., Miroy, G. J., Dikler, S. & Kelly, J. W. Recombinant human retinol-binding protein refolding, native disulfide formation, and characterization. Protein Expr. Purif. 14, 31–37 (1998)

    Article  PubMed  Google Scholar 

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Acknowledgements

We are indebted to W. S. Blaner and M. Gottesman for RBP4-overexpressing and Rbp4 knockout mice; T. Ciaraldi and R. R. Henry for human serum samples and metabolic data; Takeda Pharmaceutical Company Limited for recombinant mouse RBP4 and M. Fujisawa for sharing unpublished data; the BIDMC DNA Array Facility for assisting with the Affimetrix array; V. Petkova for assistance with Taqman; E. Rosen, Y.-B. Kim and Y. Minokoshi for helpful suggestions; and C. Wason for technical help. We thank J. E. Smith and B. Mickelson for advice regarding incorporation of fenretinide into rodent diets. Fenretinide was provided by the R. W. Johnson Pharmaceutical Company with the assistance of the National Cancer Institute's Cancer Therapy Evaluation Program. This work was supported by grants from the NIH (B.B.K and W. Blaner), Takeda Pharmaceutical Company Limited (B.B.K.) and the American Diabetes Association (B.B.K.). T.E.G. and J.M.Z. were supported by NIH career awards, F.P. by a Swiss National Science Foundation fellowship, and N.M. by an American Heart Association fellowship.

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Author notes

  1. Loredana Quadro

    Present address: Department of Food Science, Rutgers–The State University of New Jersey, New Brunswick, New Jersey, 08901, USA

  2. Qin Yang and Timothy E. Graham: *These authors contributed equally to this work

Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Massachusetts, 02215, Boston, USA

    Qin Yang, Timothy E. Graham, Nimesh Mody, Frederic Preitner, Odile D. Peroni, Janice M. Zabolotny, Ko Kotani & Barbara B. Kahn

  2. Institute of Cancer Research, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, 10032, New York, USA

    Loredana Quadro

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Correspondence to Barbara B. Kahn.

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The project was partially supported by a research grant from Takeda Pharmaceutical Company Limited (Osaka, Japan).

Supplementary information

Supplementary Methods

Methods, including animal husbandry and diet; microarray analysis; measurement of metabolic parameters, insulin tolerance tests (ITT), glucose tolerance tests (GTT); and expression and purification of recombinant hRBP4. (DOC 27 kb)

Supplementary Tables S1-S2

Supplementary Table S1 shows the clinical parameters of human subjects. Supplementary Table S2 shows metabolic parameters of RBP4 transgenic and Rbp4 knockout mice. (DOC 72 kb)

Supplementary Figures S1-S2

Supplementary Figure S1 shows a correlation between serum RBP4 levels and insulin levels in obese mice on a high-fat diet. Supplementary Figure S2 shows western blot data comparing serum RBP4 levels in the mouse models that were studied. (PPT 34 kb)

Supplementary Figure Legends S1-S2 (DOC 25 kb)

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Yang, Q., Graham, T., Mody, N. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005). https://doi.org/10.1038/nature03711

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