Intracerebroventricular administration of insulin and glucose inhibits the anorectic action of leptin in rats
Intracerebroventricular administration of insulin and glucose inhibits the anorectic action of leptin in rats
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DOI：
10.1177/153537020322801009
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发表时间：
2003-11-01
影响因子：
3.2
通讯作者：
Eguchi, K
中科院分区：
文献类型：
--
作者：
Fujita, N;Sakamaki, H;Eguchi, K
患有葡萄糖耐受不良的肥胖个体存在高血清葡萄糖、胰岛素和瘦素水平。这些物质是大脑进食的有效抑制剂。尽管上述因素升高，肥胖受试者仍然存在过度喂养。为了阐明这一矛盾的机制，胰岛素和葡萄糖对下丘脑瘦素的厌食作用的影响进行了研究。成年雄性Sprague-Dawley大鼠（重285-320 g）用脑室内注射胰岛素、葡萄糖或盐水预处理，随后将瘦素（7.5 μ g）或磷酸盐缓冲盐水（PBS）注射到第三脑室（icv）中。在icv瘦素后24小时测量累积食物摄入量。通过蛋白质印迹法测定下丘脑信号转导和激活转录因子3（STAT 3）的酪氨酸磷酸化。在用盐水预处理并用瘦素刺激的大鼠中（盐水/LEPTIN组），食物摄入减少到盐水/PBS组的大约50%（P < 0.005）。胰岛素/LEPTIN组的食物摄入量显著高于生理盐水/ LEPTIN组（P < 0.005），并达到生理盐水/PBS组的水平。在葡萄糖预处理实验中获得了类似的数据。与生理盐水相比，icv胰岛素和葡萄糖导致瘦素诱导的STAT 3酪氨酸磷酸化减少。静脉输注胰岛素和葡萄糖并没有改变所有组的外周血糖水平。大脑中的高胰岛素或葡萄糖水平可导致瘦素抵抗，如通过食物摄入所表现的，这可能是由于瘦素受体下游的STAT 3磷酸化的减弱。
Obese individuals with glucose intolerance present with high serum levels of glucose, insulin, and leptin. These substances are potent inhibitors of feeding in the brain. Obese subjects still present with over-feeding despite elevation of the above factors. To elucidate the mechanism of this paradox, the effects of insulin and glucose on the anorectic action of leptin in the hypothalamus were examined. Adult male Sprague-Dawley rats (weighing 285-320 g) were pretreated with intracerebroventricular injection of insulin, glucose, or saline, followed by leptin (7.5 mug) or phosphate-buffered saline (PBS) injection into the third cerebral ventricle (icv). The cumulative food intakes were measured 24 hr after leptin icv. The tyrosine phosphorylation of signal transducer and activator transcription factor 3 (STAT3) in the hypothalamus was determined by Western blotting. In rats pretreated with saline and stimulated with leptin (saline/LEPTIN group), food intake diminished to about 50% of that of the saline/PBS group (P < 0.005). Food intake in the insulin/LEPTIN group was significantly higher compared with the saline/ LEPTIN group (P < 0.005) and reached the level seen in the saline/PBS group. Similar data were obtained in glucose pretreatment experiments. Insulin and glucose icv resulted in reduction of leptin-induced STAT3 tyrosine phosphorylation compared with saline. Infusion of insulin and glucose icv did not alter peripheral blood glucose levels in all groups. High insulin or glucose levels in the brain could result in leptin resistance as manifested by food intake, which is probably due to the attenuation of STAT3 phosphorylation downstream the leptin receptor.