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Metformin reverses fatty liver disease in obese, leptin-deficient mice

Nature Medicine volume 6, pages 998–1003 (2000)Cite this article

Abstract

There is no known treatment for fatty liver, a ubiquitous cause of chronic liver disease. However, because it is associated with hyperinsulinemia and insulin-resistance, insulin-sensitizing agents might be beneficial. To evaluate this possibility, insulin-resistant ob/ob mice with fatty livers were treated with metformin, an agent that improves hepatic insulin-resistance. Metformin improved fatty liver disease, reversing hepatomegaly, steatosis and aminotransferase abnormalities. The therapeutic mechanism likely involves inhibited hepatic expression of tumor necrosis factor (TNF) α and TNF-inducible factors that promote hepatic lipid accumulation and ATP depletion. These findings suggest a mechanism of action for metformin and identify novel therapeutic targets in insulin-resistant states.

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Figure 1: Effect of metformin on fatty liver disease in ob/ob mice.
Figure 2: Effect of metformin treatment on food intake and body weight.
Figure 3: Effect of metformin on gene expression by white adipose tissue.
Figure 4: Effect of metformin on increased hepatic expression of TNFα mRNA in ob/ob mice.
Figure 5: Effect of metformin on TNFα–regulated gene products

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References

  1. el-Hassan, A.Y., Ibrahim, E.M., al-Mulhim, F.A., Nabhan, A.A. & Chammas, M.Y. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical findings. Br. J. Radiol. 65, 774–778 (1992).

    Article  CAS  Google Scholar 

  2. Bellentani, S. et al. Prevalence of chronic liver disease in the general population of Northern Italy: The Dionysis study. Hepatology 20, 1442–1449 (1994).

    Article  CAS  Google Scholar 

  3. Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–455 (1999).

    Article  CAS  Google Scholar 

  4. Sheth, S.G., Gordon, F.D. & Chopar, S. Nonalcoholic steatohepatitis. Ann. Intern. Med. 126, 137–145 (1997).

    Article  CAS  Google Scholar 

  5. Matteoni, C., Younossi, Z.M. & McCullough, A. Nonalcoholic fatty liver disease: a spectrum of clinical pathological severity. Gastroenterology 116, 1413–1419 (1999).

    Article  CAS  Google Scholar 

  6. Marceau, P. et al. Liver pathology and metabolic syndrome X in severe obesity. J Clin. Endocrinol. Metab. 84, 1513–1517 (1999).

    Article  CAS  Google Scholar 

  7. Yang, S.Q., Lin, H.Z., Lane, M.D., Clemens, M. & Diehl, A.M. Obesity increases sensitivity of endotoxin liver injury: implications for pathogenesis of steatohepatitis. Proc. Natl. Acad. Sci. USA 94, 2557–2562 (1997).

    Article  CAS  Google Scholar 

  8. Kushi, A. et al. Obesity and mild hyperinsulinemia found in neuropeptide Y-U1 receptor deficient mice. Proc. Natl. Acad. Sci USA 95, 15659–15664 (1998).

    Article  CAS  Google Scholar 

  9. Shimomura, I. et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12, 3182–3194 (1998).

    Article  CAS  Google Scholar 

  10. DeFronzo, R.A., Barzilai, N. & Simonson, D.C. Mechanism of metformin action in obese and lean non-insulin dependent diabetics subjects. J. Clin. Endocrinol. Metab. 73, 1294–1301 (1991).

    Article  CAS  Google Scholar 

  11. Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. & Gerich, J.E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333, 550–554 (1995).

    Article  CAS  Google Scholar 

  12. Cusi, K., Consoli, A. & DeFronzo, R.A. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 81, 4059–4067 (1996).

    CAS  PubMed  Google Scholar 

  13. Wiernsperger, N.F. & Bailey, C.J. The anti-hyperglycemic effect of metformin. Drugs 58, 31–39 (1999).

    Article  CAS  Google Scholar 

  14. Meglasson, M.D. et al. Anti hyperglycemic actions of guanidenoalkanoic acids: 3- guanidinopropionic acid ameliorates hyperglycemia in diabetic KKAy and C57BL-6J ob/ob mice and increases glucose disappearance in rhesus monkeys. J. Pharmacol. Exp. Ther. 266, 1454–1462 (1993).

    CAS  PubMed  Google Scholar 

  15. Uysal, K.T., Wiesbrock, S.M., Marino, M.W. & Hotamisligil, G.S. Protection from obesity-induced insulin-resistance in mice lacking TNFα function. Nature 389, 610–614 (1997).

    Article  CAS  Google Scholar 

  16. Campfield, L.A., Smith, F.J. & Burn, P. The OB protein (leptin) pathway — a link between adipose tissue mass and central neural networks. Horm. Metab. Res. 28, 619–632 (1996).

    Article  CAS  Google Scholar 

  17. Rouru, J., Pesonen, V. & Koulu, M. Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats. Life Sci. 50, 1813–1820 (1992).

    Article  CAS  Google Scholar 

  18. Paolisso, G. et al. Effect of metformin on food intake in obese subjects. Eur. J. Clin. Invest. 28, 441–446 (1998).

    Article  CAS  Google Scholar 

  19. Shulman, G.I. Cellular mechanisms of insulin resistance in humans. Am. J. Cardiol. 84, 3J– 10J (1999).

    Article  CAS  Google Scholar 

  20. Holleneck, C.B., Johnston, P., Varasteh, B.B., Chen, Y.D. & Reaven, G.M. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diabete Metab. 17, 483–489 (1991).

    Google Scholar 

  21. Huupponen, R., Pyykko, K., Koulu, M. & Rouru, J. Metformin and liver glycogen synthase activity in obese Zucker rats. Res. Commun. Chem. Pathol. Pharmacol. 79, 219–227 (1993).

    CAS  PubMed  Google Scholar 

  22. Ricquier, D. Neonatal brown adipose tissue, UCP-1 and the novel uncoupling proteins. Biochem. Soc. Trans. 26, 120–123 (1998).

    Article  CAS  Google Scholar 

  23. Solomon, S.S., Mishra, S.K., Cwik, C., Rajanna, B. & Postlethwaite, A.E. Pioglitazone and metformin reverse insulin resistance induced by tumor necrosis factor-alpha in liver cells. Horm. Metab. Res. 29, 379–382 (1997).

    Article  CAS  Google Scholar 

  24. Cortez-Pinto, H. et al. Bacterial lipopolysaccharide induces uncoupling protein-2 in hepatocytes via a tumor necrosis factor alpha-dependent mechanism. Biochem. Biophys. Res. Commun. 251, 313–319 (1998).

    Article  CAS  Google Scholar 

  25. Lawler, J.F., Yin, M., Diehl, A.M., Roberts, E. & Chatterjee, S. Tumor necrosis factor- alpha stimulates the maturation of sterol regulatory element binding protein-1 through the actions of neutral sphingomyleinase. J. Biol. Chem. 273, 5053–5059 (1998).

    Article  CAS  Google Scholar 

  26. Chavin, K. et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J. Biol. Chem. 274, 5692–5700 (1999).

    Article  CAS  Google Scholar 

  27. Zaibi, M.D. et al. Metformin induces an agonist-specific increase in albumin production by primary cultured rat hepatocytes. Biochem. Pharmacol. 50, 775–780 (1995).

    Article  CAS  Google Scholar 

  28. Shimomura, I., Bashmakow, Y. & Horton, J.D. Increased nuclear levels of SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274, 30028–30032 (1999).

    Article  CAS  Google Scholar 

  29. Perriello, G. et al. Acute anti hyperglycemic actions of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 43, 920–928 (1994).

    Article  CAS  Google Scholar 

  30. Purrello, F. et al. Metformin enhances certain insulin actions in cultured rat hepatoma cells. Diabetologia 31, 385–389 (1988).

    Article  CAS  Google Scholar 

  31. Melin, B. et al. Dual effect of metformin in cultured rat hepatocytes: potentiation of insulin action and prevention of insulin-induced resistance. Metabolism 39, 1089–1095 (1990).

    Article  CAS  Google Scholar 

  32. Hotamisligil, G.S. et al. IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665–668 (1996).

    Article  CAS  Google Scholar 

  33. McClain, C.J., Hill, D.B., Schmidt, J. & Diehl, A.M. Cytokines and alcoholic liver disease. Semin. Liv. Dis. 13, 170–182 (1993).

    Article  CAS  Google Scholar 

  34. Yin, M. et al. Essential role of tumor necrosis factor-alpha in alcohol-induced liver injury in mice. Gastroenterology 117, 942–952 (1999).

    Article  CAS  Google Scholar 

  35. Shimomura, E., Bashmakov, Y. & Horton, J.D. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. J. Biol. Chem. 274, 30028–30032 (1999).

    Article  CAS  Google Scholar 

  36. Cortez-Pinto, H., Lin, H.Z., Yang, S.Q., Odwin da Costa, S. & Diehl, A.M. Lipids up- regulate uncoupling protein-2 expression in rat hepatocytes. Gastroenterology 116, 1184–1193 (1999).

    Article  CAS  Google Scholar 

  37. Ni, N. & Yager, J. Co-mitogenic effects of estrogens on DNA synthesis induced by various growth factors in cultured female hepatocytes. Hepatology 19, 182–190 (1994).

    Article  Google Scholar 

  38. Diehl, A.M. et al. Tumor necrosis factor induces c-jun during the regenerative response to liver injury. Am. J. Physiol. 267, G552–G561 (1994).

    CAS  PubMed  Google Scholar 

  39. Pizer, E.S. et al. Malonyl-coenzyme A is a potential mediator of cytotoxicity induced by fatty acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 60, 213–218 (2000).

    CAS  PubMed  Google Scholar 

  40. Chomczynski, P., Sacchi, N. Single step method of RNA isolation by acid guanidine thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–161 (1987).

    Article  CAS  Google Scholar 

  41. Yang, S.Q. et al. Mitochondrial adaptations to oxidative stress in obesity-related fatty livers. Arch. Biochem. Biophys. 378, 259–268 (2000).

    Article  CAS  Google Scholar 

  42. Lavery, D.J. & Schibler, U. Circadian transcription of the 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP. Genes Dev. 7, 1871–1884 (1993).

    Article  CAS  Google Scholar 

  43. Dawson, P.A. et al. Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor SP1. J. Biol. Chem. 263, 3372–3379 (1988).

    CAS  PubMed  Google Scholar 

  44. Alo, P.L. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77, 474–482 (1996).

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Departments of Medicine, Bldg AA, Room 154-A, 4940 Eastern Ave, Baltimore, 21224, Maryland

    Hui Zhi Lin, Shi Qi Yang, Christine Chuckaree & Anna Mae Diehl

  2. Department of Pathology, Bldg AA, Room 154-A, 4940 Eastern Ave, Baltimore, 21224, Maryland

    Francis Kuhajda

  3. Department of Neuroscience & Neurology, PCTB 1007, 725 N. Wolfe St., Baltimore, 21205, Maryland

    Gabriele Ronnet

  4. The Johns Hopkins University, Baltimore, Maryland

    Gabriele Ronnet

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  1. Hui Zhi Lin
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Correspondence to Anna Mae Diehl.

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Lin, H., Yang, S., Chuckaree, C. et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 6, 998–1003 (2000). https://doi.org/10.1038/79697

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