Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance
Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance
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DOI：
10.1152/ajpendo.00203.2004
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发表时间：
2005-02-01
影响因子：
5.1
通讯作者：
Bergman, RN
中科院分区：
文献类型：
--
作者：
Kabir, M;Catalano, KJ;Bergman, RN
中枢性肥胖增加导致肝脏胰岛素抵抗的机制尚不清楚。“门静脉假说”暗示内脏脂肪的脂溶活性增加，因此增加了游离脂肪酸（FFA）向肝脏的输送，最终导致肝脏胰岛素抵抗。为了在转录水平上验证门脉假说，我们研究了脂肪喂养的内脏肥胖狗模型与对照组（n = 6）中涉及葡萄糖和脂质代谢的几个基因的表达。研究人员从吃了12周中等脂肪（42%的热量来自脂肪，n = 6）或控制饮食（35%的热量来自脂肪）的狗身上获得组织样本。Northern blot分析显示，内脏与皮下脂蛋白脂肪酶（LPL）和过氧化物酶体增殖物激活受体- γ (PPARgamma) mRNA表达比（v/s比）均有所增加。此外，脂肪喂养的狗体内，脂肪调节元件结合转录因子-1 （SREBP-1）的比例往往更高，这表明内脏脂肪库中的脂肪积累增加。激素敏感脂肪酶（HSL）的v/s比显著增加，暗示尽管高胰岛素血症，肥胖犬内脏脂肪的脂肪分解率更高。在脂肪喂养的狗中，肝脏SREBP-1表达显著升高，并有脂肪酸结合蛋白（FABP）表达升高的趋势。葡萄糖-6-磷酸酶（G-6-Pase）和磷酸烯醇丙酮酸羧激酶（PEPCK）显著升高，与糖异生增强一致。脂肪喂养动物的肝脏甘油三酯含量比对照组高45%。此外，脂肪喂养的狗的胰岛素受体结合降低了50%。内脏脂肪中促进脂质积累和脂质分解的基因表达增加，以及肝脏中限制速率的糖异生酶表达升高，与门脉理论一致。需要进行进一步的研究来确定FFA是否直接参与这一途径，以及其他信号（体液和/或神经信号）是否可能促进内脏型肥胖中肝脏胰岛素抵抗的发展。
The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls ( n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPARgamma). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein ( FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase ( PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals ( either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.