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Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2


Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

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Figure 1: Target-specific effects of aP2 inhibition on MCP-1 production in macrophages.
Figure 2: Atherosclerosis in Apoe -/- mice treated with the aP2 inhibitor.
Figure 3: Effects of aP2 inhibitor on lipid accumulation, cholesterol efflux and inflammatory responses in macrophages.
Figure 4: Metabolic studies in aP2-inhibitor-treated adipocytes and ob/ob mice.
Figure 5: Effects of aP2 inhibitor in adipose tissue of ob/ob mice.
Figure 6: Effects of aP2 inhibitor in liver of ob/ob mice.


  1. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006)

    Article  ADS  CAS  Google Scholar 

  2. Hertzel, A. V. & Bernlohr, D. A. The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol. Metab. 11, 175–180 (2000)

    Article  CAS  Google Scholar 

  3. Hunt, C. R., Ro, J. H., Dobson, D. E., Min, H. Y. & Spiegelman, B. M. Adipocyte P2 gene: developmental expression and homology of 5′-flanking sequences among fat cell-specific genes. Proc. Natl Acad. Sci. USA 83, 3786–3790 (1986)

    Article  ADS  CAS  Google Scholar 

  4. Melki, S. A. & Abumrad, N. A. Expression of the adipocyte fatty acid-binding protein in streptozotocin-diabetes: effects of insulin deficiency and supplementation. J. Lipid Res. 34, 1527–1534 (1993)

    CAS  PubMed  Google Scholar 

  5. Distel, R. J., Robinson, G. S. & Spiegelman, B. M. Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. J. Biol. Chem. 267, 5937–5941 (1992)

    CAS  PubMed  Google Scholar 

  6. Hotamisligil, G. S. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 1377–1379 (1996)

    Article  ADS  CAS  Google Scholar 

  7. Uysal, K. T., Scheja, L., Wiesbrock, S. M., Bonner-Weir, S. & Hotamisligil, G. S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141, 3388–3396 (2000)

    Article  CAS  Google Scholar 

  8. Scheja, L. et al. Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice. Diabetes 48, 1987–1994 (1999)

    Article  CAS  Google Scholar 

  9. Makowski, L. et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Med. 7, 699–705 (2001)

    Article  CAS  Google Scholar 

  10. Kazemi, M. R., McDonald, C. M., Shigenaga, J. K., Grunfeld, C. & Feingold, K. R. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler. Thromb. Vasc. Biol. 25, 1220–1224 (2005)

    Article  CAS  Google Scholar 

  11. Fu, Y., Luo, N. & Lopes-Virella, M. F. Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J. Lipid Res. 41, 2017–2023 (2000)

    CAS  PubMed  Google Scholar 

  12. Pelton, P. D., Zhou, L., Demarest, K. T. & Burris, T. P. PPARγ activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochem. Biophys. Res. Commun. 261, 456–458 (1999)

    Article  CAS  Google Scholar 

  13. Boord, J. B. et al. Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 22, 1686–1691 (2002)

    Article  CAS  Google Scholar 

  14. Sulsky, R. et al. Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg. Med. Chem. Lett. (in the press)

  15. Makowski, L., Brittingham, K. C., Reynolds, J. M., Suttles, J. & Hotamisligil, G. S. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor γ and IκB kinase activities. J. Biol. Chem. 280, 12888–12895 (2005)

    Article  CAS  Google Scholar 

  16. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002)

    Article  ADS  CAS  Google Scholar 

  17. Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 103, 10741–10746 (2006)

    Article  ADS  CAS  Google Scholar 

  18. Maeda, K. et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab. 1, 107–119 (2005)

    Article  CAS  Google Scholar 

  19. Cao, H. et al. Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice. Diabetes 55, 1915–1922 (2006)

    Article  CAS  Google Scholar 

  20. Llaverias, G. et al. Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Biochem. Biophys. Res. Commun. 318, 265–274 (2004)

    Article  CAS  Google Scholar 

  21. Fu, Y., Luo, N., Lopes-Virella, M. F. & Garvey, W. T. The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. Atherosclerosis 165, 259–269 (2002)

    Article  CAS  Google Scholar 

  22. Fisher, R. M. et al. Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals. Diabetologia 44, 1268–1273 (2001)

    Article  CAS  Google Scholar 

  23. Tuncman, G. et al. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc. Natl Acad. Sci. USA 103, 6970–6975 (2006)

    Article  ADS  CAS  Google Scholar 

  24. Sethi, J. K. et al. Characterisation of receptor-specific TNFα functions in adipocyte cell lines lacking type 1 and 2 TNF receptors. FEBS Lett. 469, 77–82 (2000)

    Article  CAS  Google Scholar 

  25. Babaev, V. R., Patel, M. B., Semenkovich, C. F., Fazio, S. & Linton, M. F. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice. J. Biol. Chem. 275, 26293–26299 (2000)

    Article  CAS  Google Scholar 

  26. Kim, J. K. et al. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J. Clin. Invest. 105, 1791–1797 (2000)

    Article  CAS  Google Scholar 

  27. Blasi, E. et al. Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus. Nature 318, 667–670 (1985)

    Article  ADS  CAS  Google Scholar 

  28. Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959)

    Article  CAS  Google Scholar 

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This work was supported in part by grants from the NIH and the American Diabetes Association. M.F. is supported by a JSPS Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science. G.T. is supported by a fellowship from the Iacocca Foundation.

Author Contributions G.S.H. designed and supervised experiments and analysed data. M.F. designed and performed experiments and analysed data. G.T., C.Z.G., E.V. and K.K. performed experiments. L.M. and G.A. developed cell lines from mice. V.R.B., S.F. and M.F.L. analysed lipoprotein profiles and advised on experiments. R.S., J.A.R. and R.A.P developed the aP2 inhibitor, BMS309403. M.F. and G.S.H wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Gökhan S. Hotamisligil.

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[COMPETING INTERESTS STATEMENT: R.S., J.A.R. and R.A.P are employed by the Bristol–Myers Squibb (BMS) Pharmaceutical Research Institute, a for-profit company developing drugs to treat the diseases in question. BMS developed the aP2 inhibitor, BMS309403, used in this study. G.S.H. has joint intellectual property on the use of aP2 inhibitor in diabetes and atherosclerosis.]

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Furuhashi, M., Tuncman, G., Görgün, C. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959–965 (2007).

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