Torsoni Márcio A, Carvalheira José B, Pereira-Da-Silva Márcio, de Carvalho-Filho Marco A, Saad Mário J A, Velloso Lício A
Department of Internal Medicine, State University of Campinas, Brazil.
Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E216-23. doi: 10.1152/ajpendo.00031.2003. Epub 2003 Mar 18.
Insulin and leptin act in the hypothalamus, providing robust anorexigenic signals. The exposure of homeothermic animals to a cold environment leads to increased feeding, accompanied by sustained low levels of insulin and leptin. In the present study, the initial and intermediate steps of the insulin-signaling cascade were evaluated in the hypothalamus of cold-exposed Wistar rats. By immunohistochemistry, most insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) immunoreactivity localized to the arcuate nucleus. Basal levels of tyrosine phosphorylation of IR and IRS-2 were increased in cold-exposed rats compared with rats maintained at room temperature. However, after an acute, peripheral infusion of exogenous insulin, significantly lower increases of IR and IRS-2 tyrosine phosphorylation were detected in the hypothalamus of cold-exposed rats. Insulin-induced association of p85/phosphatidylinositol 3-kinase with IRS-2, Ser473 phosphorylation of Akt, and tyrosine phosphorylation of ERK was significantly reduced in the hypothalamus of cold-exposed rats. To test the hypothesis of functional impairment of insulin signaling in the hypothalamus, intracerebroventricularly cannulated rats were acutely treated with insulin, and food ingestion was measured over a period of 12 h. Cold-exposed animals presented a significantly lower insulin-induced reduction in food consumption compared with animals maintained at room temperature. Hence, the present studies reveal that animals exposed to cold are resistant, both at the molecular and the functional level, to the actions of insulin in the hypothalamus.
胰岛素和瘦素在下丘脑发挥作用，提供强大的厌食信号。恒温动物暴露于寒冷环境会导致进食增加，同时胰岛素和瘦素水平持续较低。在本研究中，对暴露于寒冷环境的Wistar大鼠下丘脑胰岛素信号级联反应的初始和中间步骤进行了评估。通过免疫组织化学方法，大多数胰岛素受体（IR）和胰岛素受体底物2（IRS-2）免疫反应定位于弓状核。与饲养在室温下的大鼠相比，暴露于寒冷环境的大鼠IR和IRS-2酪氨酸磷酸化的基础水平有所增加。然而，在外周急性输注外源性胰岛素后，在暴露于寒冷环境的大鼠下丘脑中检测到IR和IRS-2酪氨酸磷酸化的增加显著较低。在暴露于寒冷环境的大鼠下丘脑中，胰岛素诱导的p85/磷脂酰肌醇3激酶与IRS-2的结合、Akt的Ser473磷酸化以及ERK的酪氨酸磷酸化均显著降低。为了检验下丘脑胰岛素信号功能受损的假说，对脑室内插管的大鼠进行急性胰岛素处理，并在12小时内测量食物摄入量。与饲养在室温下的动物相比，暴露于寒冷环境的动物胰岛素诱导的食物消耗减少明显更低。因此，本研究表明，暴露于寒冷环境的动物在分子和功能水平上均对下丘脑胰岛素的作用产生抵抗。
