Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production
Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production
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DOI：
10.1016/j.cmet.2007.05.004
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发表时间：
2007-06-01
期刊：
影响因子：
29
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
--
作者：
Koenner, A. Christine;Janoschek, Ruth;Bruening, Jens C.
中枢神经系统中的胰岛素作用调节能量稳态和葡萄糖代谢。为了定义介导这些作用的胰岛素反应性神经元，我们在促蛋白酶素（POMC）或Agouti相关的肽（AGRP）中产生了胰岛素受体（IR）的选择性失活（IR） - 表达神经元的神经元的神经元下丘脑。尽管POMC-和AGRP限制的IR基因敲除小鼠均表现出改变的能量稳态，但在AGRP-IR敲除（IR AAGRP）小鼠中，胰岛素通常未能抑制胰岛血糖 - 高磷脂夹。这些小鼠还表现出胰岛素刺激的肝介体-6表达降低，并增加了葡萄糖-6-磷酸酶的肝表达。这些结果直接表明，pomc和农业细胞中的胰岛素作用不需要稳态调节食物摄入和体重。但是，专门在表达AGRP神经元中的胰岛素作用确实在控制肝葡萄糖产生中起着关键作用，并可能为治疗2型糖尿病中胰岛素抵抗的靶标提供了关键作用。
Insulin action in the central nervous system regulates energy homeostasis and glucose metabolism. To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-iR knockout (IR AAgRP) mice. These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. These results directly demonstrate that insulin action in POMC and AgRIP cells is not required for steady-state regulation of food intake and body weight. However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes.