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.
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