Leptin deficiency Per se dictates body composition and insulin action in ob/ob mice
Leptin deficiency Per se dictates body composition and insulin action in ob/ob mice
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DOI：
10.1111/j.1365-2826.2007.01626.x
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Pijl, H.
中科院分区：
文献类型：
--
作者：
van den Hoek, A. M.;Teusink, B.;Pijl, H.
肥胖的人通常是胰岛素和瘦素抵抗。由于瘦素可以影响葡萄糖代谢，因此可以想象缺乏瘦素信号转导有助于胰岛素抵抗。目前尚不清楚瘦素是否通过外周和/或中枢机制途径影响葡萄糖代谢。在本研究中，我们的目的是：（i）确定缺乏瘦素信号转导和肥胖对胰岛素抵抗的相对贡献，（ii）建立中枢瘦素作用对葡萄糖代谢的影响。为了解决第一点，ob/ob小鼠受到严格的热量限制，使它们的体重变得与野生型小鼠相似。在肥胖ob/ob、瘦（食物限制）ob/ob和瘦的体重匹配的野生型小鼠中测量胰岛素敏感性。为了解决第二点，瘦素（或车辆）i. c. v.注入到ob/ob小鼠的侧脑室和胰岛素敏感性进行了测定。高胰岛素血症正常血糖钳夹用于定量胰岛素敏感性。食物限制几乎不影响身体成分，尽管它大大减少了体重。胰岛素在瘦型ob/ob小鼠中抑制肝葡萄糖生成（HGP）的程度大于肥胖型ob/ob小鼠，但其影响仍显著小于野生型小鼠（瘦型、肥胖型ob/ob和野生型小鼠的抑制%分别为：11.8 +/- 8.9 vs 1.3 +/- 1.1 vs 56.6 +/- 13.0%/nmol; P < 0.05）。瘦型ob/ob小鼠的胰岛素介导的葡萄糖处置（GD）也介于肥胖型ob/ob小鼠和野生型小鼠之间（分别为37.5 +/- 21.4 vs 25.1 +/- 14.6 vs 59.6 +/- 17.3 μ mol/min/kg/nmol胰岛素;野生型vs肥胖型ob/ob小鼠P < 0.05）。在ob/ob小鼠中，瘦素输注急性增强了肝脏胰岛素敏感性（胰岛素诱导的HGP抑制）和胰岛素介导的GD（胰岛素分别为9.1 +/- 2.4 vs 5.0 +/- 2.7%/nmol，胰岛素分别为25.6 +/- 5.6 vs 13.6 +/- 4.8 μ mol/min/kg/nmol;两种比较均P < 0.05）。瘦素信号的缺乏和肥胖都可能导致肥胖个体的胰岛素抵抗。中枢瘦素信号传导的减少可以严重影响这些个体的葡萄糖代谢。
Obese humans are often insulin- and leptin resistant. Since leptin can affect glucose metabolism, it is conceivable that a lack of leptin signal transduction contributes to insulin resistance. It remains unclear whether leptin affects glucose metabolism via peripheral and/or central mechanistic routes. In the present study, we aimed: (i) to determine the relative contributions of lack of leptin signal transduction and adiposity to insulin resistance and (ii) to establish the impact of central leptin action on glucose metabolism. To address the first point, ob/ob mice were subjected to severe calorie restriction, so that their body weight became similar to that of wild-type mice. Insulin sensitivity was measured in obese ob/ob, lean (food restricted) ob/ob and lean, weight-matched wild-type mice. To address the second point, leptin (or vehicle) was i.c.v. infused to the lateral cerebral ventricle of ob/ob mice and insulin sensitivity was determined. Hyperinsulinaemic euglyceamic clamps were used to quantify insulin sensitivity. Food restriction barely affected body composition, although it profoundly curtailed body weight. Insulin suppressed hepatic glucose production (HGP) to a greater extent in lean ob/ob than in obese ob/ob mice, but its impact remained considerably less than in wild-type mice (% suppression: 11.8 +/- 8.9 versus 1.3 +/- 1.1 versus 56.6 +/- 13.0%/nmol, for lean, obese ob/ob and wild-type mice, respectively; P < 0.05). The insulin-mediated glucose disposal (GD) of lean ob/ob mice was also in between that of obese ob/ob and wild-type mice (37.5 +/- 21.4 versus 25.1 +/- 14.6 versus 59.6 +/- 17.3 mu mol/min/kg/nmol of insulin, respectively; P < 0.05 wild-type versus obese ob/ob mice). Leptin infusion acutely enhanced both hepatic insulin sensitivity (insulin-induced inhibition of HGP) and insulin-mediated GD (9.1 +/- 2.4 versus 5.0 +/- 2.7%/nmol of insulin, and 25.6 +/- 5.6 versus 13.6 +/- 4.8 mu mol/min/kg/nmol of insulin, respectively; P < 0.05 for both comparisons) in ob/ob mice. Both a lack of leptin signals and adiposity may contribute to insulin resistance in obese individuals. Diminution of central leptin signalling can critically affect glucose metabolism in these individuals.