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Regulation of Metabolic Responses by Adipocyte/ Macrophage Fatty Acid–Binding Proteins in Leptin-Deficient Mice

¹ Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts
² Department of Internal Medicine, Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
³ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

Address correspondence and reprint requests to Gökhan S. Hotamisligil, MD, PhD, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: ghotamis{at}hsph.harvard.edu

Abbreviations: AMPK, AMP-activated kinase; FABP, fatty acid–binding protein; HGP, hepatic glucose production; SCD-1, stearoyl-CoA desaturase-1; SREBP, sterol regulatory element–binding protein

Fatty acid–binding proteins (FABPs) are cytosolic fatty acid chaperones that play a critical role in systemic regulation of lipid and glucose metabolism. In animals lacking the adipocyte/macrophage FABP isoforms aP2 and mal1, there is strong protection against diet-induced obesity, insulin resistance, type 2 diabetes, fatty liver disease, and hypercholesterolemic atherosclerosis. On high-fat diet, FABP-deficient mice also exhibit enhanced muscle AMP-activated kinase (AMPK) and reduced liver stearoyl-CoA desaturase-1 (SCD-1) activities. Here, we performed a cross between aP2^–/–, mal1^–/–, and leptin-deficient (ob/ob) mice to elucidate the role of leptin action on the metabolic phenotype of aP2-mal1 deficiency. The extent of obesity in the ob/ob-aP2-mal1^–/– mice was comparable with ob/ob mice. However, despite severe obesity, ob/ob-aP2-mal1^–/– mice remained euglycemic and demonstrated improved peripheral insulin sensitivity. There was also a striking protection from liver fatty infiltration in the ob/ob-aP2-mal1^–/– mice with strong suppression of SCD-1 activity. On the other hand, the enhanced muscle AMPK activity in aP2-mal1^–/– mice was lost in the ob/ob background. These results indicated that both decreased body weight and enhanced muscle AMPK activity in aP2-mal1^–/– mice are potentially leptin dependent but improved systemic insulin sensitivity and protection from liver fatty infiltration are largely unrelated to leptin action and that insulin-sensitizing effects of FABP deficiency are, at least in part, independent of its effects on total-body adiposity.

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