Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats
Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats
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DOI：
10.1016/s0306-4522(01)00142-7
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发表时间：
2001-01-01
期刊：
影响因子：
3.3
通讯作者：
Tümer, N
中科院分区：
文献类型：
--
作者：
Scarpace, PJ;Matheny, M;Tümer, N
瘦素有助于调节食物摄入和能量消耗。我们之前证明了F344 xBN大鼠。迟发性肥胖的啮齿动物模型是瘦素抗性的，并且在这些老年人中外周施用瘦素后瘦素信号转导受损。超重的老鼠为了确定瘦素信号转导是否响应于瘦素的中枢给药而受损以及下丘脑瘦素受体的减少是否可能促成受损的信号转导，我们检测了瘦素诱导的STAT 3激活的体内剂量反应，（磷酸化和对SIE M-67寡核苷酸的结合活性）在年轻和年老的迟发性肥胖大鼠中，对i. c. v.施用瘦素的反应沿着下丘脑瘦素受体蛋白的水平。瘦素诱导的STAT 3的最大磷酸化为41%，与老年肥胖大鼠相比，年轻大鼠中更大，但年轻（41 ng）和老年肥胖大鼠（47 ng）中STAT 3的半最大磷酸化所需的剂量相似。总的STAT 3蛋白没有随着瘦素或年龄的变化而变化，瘦素也没有增加STAT 1的磷酸化。瘦素增加磷酸化的STAT 3转录因子结合在年轻的8倍，但只有4倍，在老年肥胖大鼠，瘦素受体蛋白是50%，更大的年轻人相比，老年rates.These数据表明，老年超重大鼠表现出减少的信号转导响应于集中管理瘦素，可能是减少瘦素受体蛋白在老年肥胖大鼠中观察到的结果。瘦素受体减少和瘦素信号转导受损可以解释瘦素给药后老年大鼠的生理反应减少。这种受损的瘦素信号转导可能是由于随着年龄的增加肥胖或年龄本身，或两者兼而有之。(C)2001年IBRO。由爱思唯尔科技有限公司出版。保留所有权利。
Leptin contributes to the regulation of both food intake and energy expenditure. We previously demonstrated that the F344xBN rat. a rodent model for late-onset obesity, is leptin-resistant and that leptin signal transduction following peripheral administration of leptin is impaired in these aged. overweight rats. To determine if leptin signal transduction is impaired in response to central administration of leptin and whether reduced hypothalamic leptin receptors may be contributing to the impaired signal transduction, we examined the in vivo dose-response leptin-induced STAT3 activation (phosphorylation and binding activity to the SIE M-67 oligonucleotide) in response to i.c.v. administration of leptin along with the level of hypothalamic leptin receptor protein in young and older, late-onset obese rats. The leptin-induced maximum phosphorylation of STAT3 was 41%, greater in young compared with older obese rats, but the dose required for half-maximal phosphorylation of STAT3 was similar in both the young (41 ng) and old-obese (47 ng) rats. There were no changes in total STAT3 protein with leptin or age, and leptin did not increase phosphorylation of STAT1. Leptin increased phosphorylation of STAT3 transcription factor binding eight-fold in the young but only four-fold in the aged-obese rats, and leptin receptor protein was 50%, greater in the young compared with aged rats.These data indicate that aged-overweight rats demonstrate reduced signal transduction in response to centrally administered leptin that may be the result of the diminished leptin receptor protein observed in the aged-obese rats. The diminished leptin receptors and impaired leptin signal transduction may explain the diminished physiological responses observed following leptin administration in older rats. This impaired leptin signal transduction may be due either to the elevated obesity with age or to age itself, or to both. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.