CNS/IGF-axis in modulation of body composition in aging

描述（由申请人提供）：随着内脏脂肪（VF）的增加，身体脂肪分布发生变化是人类衰老的标志。 VF 积累会导致代谢综合征 (MS)，包括胰岛素抵抗、高血压和血脂异常。 MS 会增加血栓形成、动脉粥样硬化、冠状动脉闭塞和中风的风险，也可能是多种癌症和阿尔茨海默病的危险因素。与心室颤动累积增加和代谢综合征风险增加同时，衰老还与生长激素 (GH) 和胰岛素样生长因子-1 (IGF-1) 的减少有关。在 IGF-1 基因缺失的个体中也观察到了与衰老类似的身体成分变化，这些人的 GH 水平升高。我们的假设是 IGF-1 对身体成分有直接影响，这些影响与调节身体成分（如瘦素和胰岛素）的其他肽类似，是通过下丘脑介导的。我们将使用一种将肽注入第三脑室并测量外周生理反应的新技术来检验这一假设。我们将长期向第三脑室注射IGF-1，研究其对身体脂肪分布、肌肉质量、能量消耗和脂肪库生物学特性的影响（通过基因阵列技术和RT-PCR）。我们将阻断 IGF-1 和胰岛素受体以及一些 IGF-1/胰岛素信号通路，以便识别 CMS 中 IGF-1 作用的受体和下游通路。在我们的初步研究中，我们还证明 IGF 结合蛋白 (IGFBP-3) 会增加内脏脂肪。使用 IGFBP-3 突变体（改变了与 IGF-1 的结合），我们将评估这种效应是否独立于与 IGF-1 的结合。我们还将评估 IGFBP-3 的作用是否通过中枢神经系统介导。我们将通过研究 c-fos 激活来研究下丘脑核团响应 IGF-1 和 IGFBP-3 的激活。由于 GH 给药对衰老受试者有不必要的副作用，因此更好地了解由于年龄相关的变化 GH/IGF-1 轴的下降可能会导致更好的策略来预防和/或逆转衰老过程早期的这一系列代谢缺陷。

DESCRIPTION (provided by applicant): Changes in body fat distribution with an increase in visceral fat (VF) is a hallmark of aging in humans. The VF accumulation leads to metabolic syndrome (MS), a constellation of insulin resistance, hypertension and dyslipidemias. MS increases the risk for thrombosis, atherosclerosis, coronary artery occlusion and stroke and may also be a risk factor for a variety of cancers and Alzheimer's disease. Parallel with the increase in accumulation of VF and the increased risk for metabolic syndrome, aging is also associated with a decrease in growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Changes in body composition, similar to aging, are also observed in individuals with IGF-1 gene deletion, who have increased levels of GH. Our hypothesis is that IGF-1 has direct effects on body composition and these effects, similar to other peptides that regulate body composition such as leptin and insulin, are mediated through the hypothalamus. We will test this hypothesis using a novel technology of infusing peptides in to the third ventricle and measuring peripheral physiologic responses. We will administer IGF-1 in to the third ventricle chronically and study the effects on body fat distribution, muscle mass, energy expenditure, and the biological characteristics of fat depots (by gene array technology and RT-PCR). We will block IGF-1 and insulin receptors and some of the IGF-1/insulin signaling pathways in order to identify the receptor and down-stream pathway for IGF-1 action in the CMS. In our preliminary studies we also demonstrate that IGF binding protein (IGFBP-3) increases visceral fat. Using IGFBP-3 mutants (that have altered binding to IGF-1) we will evaluate if this effect is independent of binding to IGF-1. We will also evaluate if the effects of IGFBP-3 are mediated through the central nervous system. We will study activation of hypothalamic nuclei in response to IGF-1 and IGFBP-3 by studying c-fos activation. Because GH administration has unwarranted side effects in aging subjects, a better understanding of the age-dependent changes due to decline in the GH/IGF-1 axis is likely to lead to better strategies to prevent and/or reverse this constellation of metabolic defects early during the aging process.