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

Nature volume 447, pages 959–965 (2007)Cite this article

Abstract

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.

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Acknowledgements

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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Author notes

  1. Liza Makowski

    Present address: Present address: Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27704, USA,

  2. Genichi Atsumi

    Present address: Present address: Clinical Molecular Biology, Teikyo University, Kanagawa 199-0195, Japan.,

Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA,

    Masato Furuhashi, Gürol Tuncman, Cem Z. Görgün, Liza Makowski, Genichi Atsumi, Eric Vaillancourt, Keita Kono & Gökhan S. Hotamisligil

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA,

    Vladimir R. Babaev, Sergio Fazio & MacRae F. Linton

  3. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA,

    Richard Sulsky, Jeffrey A. Robl & Rex A. Parker

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Correspondence to Gökhan S. Hotamisligil.

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Competing interests

[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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This file contains Supplementary Figures S1-S8 with Legends and Supplementary Tables S1-S3. (PDF 774 kb)

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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). https://doi.org/10.1038/nature05844

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