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Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance

Abstract

Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl–coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)—two candidate mediators of insulin resistance—were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, β-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle β-OH-butyrate levels and improvement of insulin sensitivity.

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Figure 1: Metabolic impact of MCD overexpression in primary hepatocytes and liver.
Figure 2: Metabolic variables in rats during hyperinsulinemic-euglycemic clamp.
Figure 3: Effect of MCD overexpression on muscle and liver insulin sensitivity.
Figure 4: Muscle triglyceride and LC-CoA levels.
Figure 5: Tandem mass spectrometry–based analysis of acylcarnitine species in muscle samples.

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References

  1. Boden, G. & Shulman, G.I. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur. J. Clin. Invest. 32, 14–23 (2002).

    Article  CAS  Google Scholar 

  2. McGarry, J.D. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7–18 (2002).

    Article  CAS  Google Scholar 

  3. Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    Article  CAS  Google Scholar 

  4. Unger, R.H. Lipotoxic diseases. Annu. Rev. Med. 53, 319–336 (2002).

    Article  CAS  Google Scholar 

  5. Buettner, R., Newgard, C.B., Rhodes, C.J. & O'Doherty, R.M. Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia. Am. J. Physiol. Endocrinol. Metab. 278, 563–569 (2000).

    Article  Google Scholar 

  6. Higa, M. et al. Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc. Natl. Acad. Sci. USA 96, 11513–11518 (1999).

    Article  CAS  Google Scholar 

  7. Mayerson, A.B. et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51, 797–802 (2002).

    Article  CAS  Google Scholar 

  8. Kim, J.K., Gavrilova, O., Chen, Y., Reitman, M.L. & Shulman, G.I. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J. Biol. Chem. 275, 8456–8460 (2000).

    Article  CAS  Google Scholar 

  9. McGarry, J.D. et al. New insights into the mitochondrial carnitine palmitoyltransferase enzyme system. Biochimie 73, 77–84 (1991).

    Article  CAS  Google Scholar 

  10. Mulder, H. et al. Overexpression of a modified human malonyl-CoA decarboxylase blocks the glucose-induced increase in malonyl-CoA level but has no impact on insulin secretion in INS-1-derived (832/13) beta-cells. J. Biol. Chem. 276, 6479–6484 (2001).

    Article  CAS  Google Scholar 

  11. Herz, J. & Gerard, R.D. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc. Natl. Acad. Sci. USA 90, 2812–2816 (1993).

    Article  CAS  Google Scholar 

  12. O'Doherty, R.M., Lehman, D.L., Telemaque-Potts, S. & Newgard, C.B. Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes 48, 2022–2027 (1999).

    Article  CAS  Google Scholar 

  13. Chu, A.C. et al. Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats. Am. J. Physiol. (in the press).

  14. Millington, D.S., Kodo, N., Norwood, D.L. & Roe, C.R. Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J. Inherit. Metab. Dis. 13, 321–324 (1990).

    Article  CAS  Google Scholar 

  15. Holness, M.J. & Sugden, M.C. Glucose disposal by skeletal muscle in response to re-feeding after progressive starvation. Biochem. J. 277 (part 2), 429–433 (1991).

    Article  CAS  Google Scholar 

  16. Ruderman, N.B., Goodman, M.N., Berger, M. & Hagg, S. Effect of starvation on muscle glucose metabolism: studies with the isolated perfused rat hindquarter. Fed. Proc. 36, 171–176 (1977).

    CAS  Google Scholar 

  17. Goodpaster, B.H., He, J., Watkins, S. & Kelley, D.E. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J. Clin. Endocrinol. Metab. 86, 5755–5761 (2001).

    Article  CAS  Google Scholar 

  18. Hoppeler, H. et al. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J. Appl. Physiol. 59, 320–327 (1985).

    Article  CAS  Google Scholar 

  19. Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230–50236 (2002).

    Article  CAS  Google Scholar 

  20. Aguirre, V. et al. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J. Biol. Chem. 277, 1531–1537 (2002).

    Article  CAS  Google Scholar 

  21. Leone, T.C., Weinheimer, C.J. & Kelly, D.P. A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. USA 96, 7473–7478 (1999).

    Article  CAS  Google Scholar 

  22. Guerre-Millo, M. et al. PPAR-α-null mice are protected from high-fat diet-induced insulin resistance. Diabetes 50, 2809–2814 (2001).

    Article  CAS  Google Scholar 

  23. Tordjman, K. et al. PPARα deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J. Clin. Invest. 107, 1025–1034 (2001).

    Article  CAS  Google Scholar 

  24. Muoio, D.M. et al. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice - Evidence for compensatory regulation by PPAR δ. J. Biol. Chem. 277, 26089–26097 (2002).

    Article  CAS  Google Scholar 

  25. Randle, P.J., Newsholme, E.A. & Garland, P.B. Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem. J. 93, 652–665 (1964).

    Article  CAS  Google Scholar 

  26. Singh, B.M., Krentz, A.J. & Nattrass, M. Insulin resistance in the regulation of lipolysis and ketone body metabolism in non-insulin dependent diabetes is apparent at very low insulin concentrations. Diabetes Res. Clin. Pract. 20, 55–62 (1993).

    Article  CAS  Google Scholar 

  27. Russell, R.R., III & Taegtmeyer, H. Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate. J. Clin. Invest. 87, 384–390 (1991).

    Article  CAS  Google Scholar 

  28. Russell, R.R., III & Taegtmeyer, H. Coenzyme A sequestration in rat hearts oxidizing ketone bodies. J. Clin. Invest. 89, 968–973 (1992).

    Article  CAS  Google Scholar 

  29. Tardif, A. et al. Chronic exposure to beta-hydroxybutyrate impairs insulin action in primary cultures of adult cardiomyocytes. Am. J. Physiol. Endocrinol. Metab. 281, E1205–E1212 (2001).

    Article  CAS  Google Scholar 

  30. Patti, M.E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl. Acad. Sci. USA 100, 8466–8471 (2003).

    Article  CAS  Google Scholar 

  31. Petersen, K.F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).

    Article  CAS  Google Scholar 

  32. Mascaro, C., Buesa, C., Ortiz, J.A., Haro, D. & Hegardt, F.G. Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. Arch. Biochem. Biophys. 317, 385–390 (1995).

    Article  CAS  Google Scholar 

  33. Abu-Elheiga, L., Oh, W., Kordari, P. & Wakil, S.J. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc. Natl. Acad. Sci. USA 100, 10207–10212 (2003).

    Article  CAS  Google Scholar 

  34. Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A. & Wakil, S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613–2616 (2001).

    Article  CAS  Google Scholar 

  35. Abu-Elheiga, L. et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl. Acad. Sci. USA 97, 1444–1449 (2000).

    Article  CAS  Google Scholar 

  36. 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  Google Scholar 

  37. Becker, T.C. et al. Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell Biol. 43, 161–189 (1994).

    Article  CAS  Google Scholar 

  38. Massague, J. & Guinovart, J.J. Insulin control of rat hepatocyte glycogen synthase and phosphorylase in the absence of glucose. FEBS Lett. 82, 317–320 (1977).

    Article  CAS  Google Scholar 

  39. Antinozzi, P.A., Segall, L., Prentki, M., McGarry, J.D. & Newgard, C.B. Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion. A re-evaluation of the long-chain acyl-CoA hypothesis. J. Biol. Chem. 273, 16146–16154 (1998).

    Article  CAS  Google Scholar 

  40. Lee, Y. et al. Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 46, 408–413 (1997).

    Article  CAS  Google Scholar 

  41. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).

    Article  CAS  Google Scholar 

  42. Shao, J., Yamashita, H., Qiao, L. & Friedman, J.E. Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J. Endocrinol. 167, 107–115 (2000).

    Article  CAS  Google Scholar 

  43. Summers, S.A., Whiteman, E.L., Cho, H., Lipfert, L. & Birnbaum, M.J. Differentiation-dependent suppression of platelet-derived growth factor signaling in cultured adipocytes. J. Biol. Chem. 274, 23858–23867 (1999).

    Article  CAS  Google Scholar 

  44. Milburn, J.L. Jr. et al. Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J. Biol. Chem. 270, 1295–1299 (1995).

    Article  CAS  Google Scholar 

  45. Newgard, C.B., Moore, S.V., Foster, D.W. & McGarry, J.D. Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway. J. Biol. Chem. 259, 6958–6963 (1984).

    CAS  Google Scholar 

  46. McGarry, J.D., Stark, M.J. & Foster, D.W. Hepatic malonyl-CoA levels of fed, fasted and diabetic rat liver as measured using a simple radioisotopic assay. J. Biol. Chem. 253, 8291–8293 (1978).

    CAS  Google Scholar 

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Acknowledgements

These studies were supported by grants from Takeda Chemicals Industries, the Donald W. Reynolds Foundation and the National Institutes of Health (P01 DK58398). We are grateful to P. Anderson, K. Ross and H. Winfield for outstanding technical assistance.

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Correspondence to Christopher B Newgard.

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An, J., Muoio, D., Shiota, M. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10, 268–274 (2004). https://doi.org/10.1038/nm995

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