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

CNS/IGF 轴在衰老过程中调节身体成分

基本信息

批准号：
7896468
负责人：
Radhika Hiren Muzumdar
金额：
$ 12.79万
依托单位：
MONTEFIORE MEDICAL CENTER (BRONX, NY)
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7896468
关键词：
Adverse effects Age Aging Aging-Related Process Alzheimer&apos s Disease Antibodies Atherosclerosis Binding Biologic Characteristic Biological Body Composition Body Weight Body fat Brain Cell Nucleus Characteristics Chronic Conscious Coronary artery Data Defect Deterioration Dyslipidemias Eating Energy Intake Energy Metabolism FOS gene Fatty acid glycerol esters Functional disorder Gene Deletion Genes Human Hypertension Hypothalamic structure IGF1 gene IGFBP3 gene In Vitro Individual Infusion procedures Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Intake Investigation Lead Leptin Malignant Neoplasms Measures Mediating Metabolic Metabolic syndrome Mitogen-Activated Protein Kinases Molecular Monitor Neuraxis Pathway interactions Peptides Peripheral Phosphotransferases Physiological Physiology Rattus Relative (related person)Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Saline Somatotropin Specificity Stream Stroke Techniques Technology Testing Third ventricle structure Thrombosis Visceral age effect age related artery occlusion base in vivo kinase inhibitor muscle form mutant new technology novel prevent receptor response subcutaneous

项目摘要

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.

描述（由申请人提供）：随着内脏脂肪（VF）的增加，体内脂肪分布的变化是人类衰老的标志。 VF积累导致代谢综合征（MS），这是胰岛素抵抗，高血压和血脂异常的星座。 MS增加了血栓形成，动脉粥样硬化，冠状动脉阻塞和中风的风险，也可能是各种癌症和阿尔茨海默氏病的危险因素。与VF的积累增加以及代谢综合征的增加相似，衰老也与生长激素（GH）和胰岛素样生长因子1（IGF-1）的降低有关。在患有GH水平升高的IGF-1基因缺失的个体中，人体成分的变化（类似于衰老）也会观察到。我们的假设是，IGF-1对人体组成有直接的影响，这些作用类似于调节人体组成（例如瘦素和胰岛素）的其他肽，是通过下丘脑介导的。我们将使用新颖的技术将肽注入第三个心室并测量周围生理反应的新技术来检验这一假设。我们将长期对第三个心室进行IGF-1，并研究对体内脂肪分布，肌肉质量，能量消耗以及脂肪仓库的生物学特征的影响（通过Gene Array Technology和RT-PCR）。我们将阻止IGF-1和胰岛素受体以及一些IGF-1/胰岛素信号通路，以识别CMS中IGF-1作用的受体和下游途径。在我们的初步研究中，我们还证明了IGF结合蛋白（IGFBP-3）会增加内脏脂肪。使用IGFBP-3突变体（已改变与IGF-1的结合），我们将评估该效果是否与与IGF-1的结合无关。我们还将评估IGFBP-3的影响是否是通过中枢神经系统介导的。我们将通过研究C-FOS激活来研究下丘脑核对IGF-1和IGFBP-3的激活。因为GH管理在老龄化受试者中没有任何副作用，所以更好地理解了年龄的变化在老龄化过程中，GH/IGF-1轴的下降可能会导致更好的策略来预防和/或扭转这一代谢缺陷的星座。