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Partial Gene Deletion of Heart-Type Fatty Acid–Binding Protein Limits the Severity of Dietary-Induced Insulin Resistance

¹ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
² Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee
³ Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

The aim of this study was to determine the contribution of heart-type fatty acid–binding protein (H-FABP) to glucose and long-chain fatty acid (LCFA) utilization in dietary-induced insulin resistance. We tested the hypothesis that H-FABP facilitates increases in LCFA flux present in glucose-intolerant states and that a partial reduction in the amount of this protein would compensate for all or part of the impairment. Transgenic H-FABP heterozygotes (HET) and wild-type (WT) littermates were studied following chow diet (CHD) or high-fat diet (HFD) for 12 weeks. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions, respectively. Following 5 days of recovery, mice received either a saline infusion or underwent a euglycemic insulin clamp (4 mU · kg^–1 · min^–1) for 120 min. At 90 min, a bolus of 2-deoxyglucose and [¹²⁵I]-15-(-iodophenyl)-3-R,S-methylpentadecanoic acid were administered to obtain indexes of glucose and LCFA utilization. At 120 min, skeletal muscles were excised for tracer determination. All HFD mice were obese and hyperinsulinemic; however, only HFD-WT mice were hyperglycemic. Glucose infusion rates during insulin clamps were 49 ± 4, 59 ± 4, 16 ± 4, and 33 ± 4 mg · kg^–1 · min^–1 for CHD-WT, CHD-HET, HFD-WT, and HFD-HET mice, respectively, showing that HET limited the severity of whole-body insulin resistance with HFD. Insulin-stimulated muscle glucose utilization was attenuated in HFD-WT but unaffected in HFD-HET mice. Conversely, rates of LCFA clearance were increased with HFD feeding in HFD-WT but not in HFD-HET mice. In conclusion, a partial reduction in H-FABP protein normalizes fasting glucose levels and improves whole-body insulin sensitivity in HFD-fed mice despite obesity.

Abbreviations: CHD, chow diet; H-FABP, heart-type fatty acid–binding protein; [³H]DG, 2-deoxy[³H]glucose; GIR, glucose infusion rate; HFD, high-fat diet; [¹²⁵I]BMIPP, [¹²⁵I]-15-(-iodophenyl)-3-R,S-methylpentadecanoic acid; LCFA, long-chain fatty acid; NEFA, nonesterified fatty acid

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