Low-Grade Hypothalamic Inflammation Leads to Defective Thermogenesis, Insulin Resistance, and Impaired Insulin Secretion
Low-Grade Hypothalamic Inflammation Leads to Defective Thermogenesis, Insulin Resistance, and Impaired Insulin Secretion
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DOI：
10.1210/en.2010-0659
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Velloso, Licio A.
中科院分区：
文献类型：
--
作者：
Arruda, Ana Paula;Milanski, Marciane;Velloso, Licio A.
下丘脑炎症存在于肥胖动物模型中，脑室内注射TNF α可以重现肥胖动物下丘脑的许多特征。由于肥胖是2型糖尿病（DM 2）的危险因素，我们假设，通过诱导下丘脑炎症，我们可以重现DM 2的一些临床特征。瘦Wistar大鼠和TNF受体1基因敲除小鼠被用来确定TNF α对产热和代谢参数的影响。通过免疫印迹和实时荧光PCR检测细胞信号转导和蛋白表达。产热进行了评估，在活体大鼠，并在离体肌纤维呼吸测定。在Wistar大鼠中，下丘脑TNF α减弱了瘦素的促凋亡作用，这伴随着瘦素信号传导减少和细胞因子信号传导抑制因子3的表达增加。此外，下丘脑TNF α减少O-2消耗和棕色脂肪组织和骨骼肌中产热蛋白的表达。此外，下丘脑炎症增加基线血浆胰岛素和分离的胰岛的胰岛素分泌，这伴随着肝脏和骨骼肌中受损的胰岛素信号转导。硬脂酸引起的下丘脑炎症也减少了O-2的消耗和钝化外周胰岛素信号转导。脑室内注射英夫利西单抗可恢复肥胖大鼠的O-2消耗，而TNF受体1敲除小鼠可免受饮食诱导的产热减少和胰岛素信号转导缺陷的影响。因此，下丘脑的低度炎症足以诱导肥胖和DM 2中通常受损的许多参数的变化，并且TNF α是该过程的重要介质。（内分泌学152：1314-1326，2011）
Hypothalamic inflammation is present in animal models of obesity, and the intracere broventricular injection of TNF alpha can reproduce a number of features of the hypothalamus of obese animals. Because obesity is a risk factor for type 2 diabetes (DM2) we hypothesized that, by inducing hypothalamic inflammation, we could reproduce some clinical features of DM2. Lean Wistar rats and TNF receptor 1-knockout mice were employed to determine the effects of hypothalamic actions of TNF alpha on thermogenesis and metabolic parameters. Signal transduction and protein expression were evaluated by immunoblot and real-time PCR. Thermogenesis was evaluated in living rats, and respirometry was determined in isolated muscle fiber. In Wistar rats, hypothalamic TNF alpha blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNF alpha reduces O-2 consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base-line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O-2 consumption and blunts peripheral insulin signal transduction. The use of intracere broventricular infliximab restores O-2 consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNF alpha is an important mediator of this process. (Endocrinology 152: 1314-1326, 2011)