Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance
Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance
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DOI：
10.2337/diabetes.54.11.3133
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发表时间：
2005-11-01
期刊：
影响因子：
7.7
通讯作者：
Rottman, JN
中科院分区：
文献类型：
--
作者：
Shearer, J;Fueger, PT;Rottman, JN
本研究的目的是确定心脏型脂肪酸结合蛋白（H-FABP）的葡萄糖和长链脂肪酸（LCFA）的利用在饮食诱导的胰岛素抵抗的贡献。我们测试了H-FABP促进葡萄糖不耐受状态下LCFA通量增加的假设，以及该蛋白量的部分减少将补偿全部或部分损害。转基因H-FABP杂合子（HET）和野生型（WT）同窝仔在普通饲料（CHD）或高脂饲料（HFD）后研究12周。通过手术将导管植入颈动脉和颈静脉中，分别用于采样和输注。恢复5天后，小鼠接受生理盐水输注或经历正葡萄糖胰岛素钳夹（4 mU（.）kg（-1 .）在90 min时，推注2-脱氧葡萄糖和[I-125]-15-（ρ-碘苯基）-3-R，S-甲基十五烷酸以获得葡萄糖和LCFA利用指数。在120分钟时，切除骨骼肌用于示踪剂测定。所有HFD小鼠均为肥胖和高胰岛素血症;然而，仅HFD-WT小鼠为高血糖。胰岛素钳夹期间的葡萄糖输注速率分别为49 +/- 4、59 +/- 4、16 +/- 4和33 +/- 4 mg（.）kg（-1）（.）min（-1），表明HET限制了HFD全身胰岛素抵抗的严重程度。胰岛素刺激的肌肉葡萄糖利用在HFD-WT中减弱，但在HFD-HET小鼠中不受影响。相反，在RFD-WT小鼠中，LCFA清除率随着HFD喂养而增加，但在HFD-HET小鼠中则没有。总之，H-FABP蛋白的部分减少使空腹血糖水平正常化，并改善HFD喂养小鼠的全身胰岛素敏感性，尽管肥胖。
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 [I-125]-15-(rho-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 RFD-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.