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

描述（由申请方提供）：伴随内脏脂肪（VF）增加的体脂分布变化是人类衰老的标志。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。MS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风险因素。与VF积累增加和代谢综合征风险增加平行，衰老也与生长激素（GH）和胰岛素样生长因子-1（IGF-1）减少相关。身体组成的变化，类似于衰老，也可以在IGF-1基因缺失的个体中观察到，他们的GH水平增加。我们的假设是，IGF-1对身体组成有直接影响，这些影响与其他调节身体组成的肽（如瘦素和胰岛素）类似，是通过下丘脑介导的。我们将使用一种新的技术，将肽注入第三脑室并测量外周生理反应来验证这一假设。我们将通过第三脑室长期注射IGF-1，研究其对体脂分布、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，我们还表明，IGF结合蛋白（IGFBP-3）增加内脏脂肪。使用IGFBP-3突变体（与IGF-1的结合发生改变），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IGF-1和IGFBP-3对下丘脑核团的激活反应。由于GH给药在老年受试者中有不必要的副作用，因此更好地了解GH给药的年龄依赖性变化， 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.