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

描述（由申请人提供）：体内脂肪分布的变化与内脏脂肪（VF）的增加是人类衰老的标志。VF积累导致代谢综合征（MS），一系列胰岛素抵抗、高血压和血脂异常。多发性硬化症增加了血栓形成、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。在VF积累增加和代谢综合征风险增加的同时，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与衰老相似的身体成分变化，这些个体的生长激素水平升高。我们的假设是，IGF-1对身体成分有直接影响，这些影响类似于其他调节身体成分的肽，如瘦素和胰岛素，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验证这一假设。我们将长期给第三心室注射IGF-1，并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，以确定在CMS中IGF-1作用的受体和下游途径。在我们的初步研究中，我们也证明了IGF结合蛋白（IGFBP-3）增加内脏脂肪。使用IGFBP-3突变体（改变了与IGF-1的结合），我们将评估这种影响是否独立于与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的激活来研究下丘脑核对IGF-1和IGFBP-3的激活。由于生长激素给药在老年受试者中有不必要的副作用，因此更好地了解年龄依赖性变化是由于

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.