1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
2. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
3. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
4. Present address: Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27704, USA
5. Present address: Clinical Molecular Biology, Teikyo University, Kanagawa 199-0195, Japan.

Correspondence to: Gökhan S. Hotamisligil¹ Correspondence and requests for materials should be addressed to G.S.H. (Email: ghotamis@hsph.harvard.edu).

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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