ABSTRACT
Biological and Genetic Factors Associated with Obesity in Hispanic Adolescents
Obesity and insulin resistance which precede Type 2 diabetes mellitus (T2DM), are associated with low grade systemic inflammation, characterized by the elevation of proinflammatory markers such as tumor necrosis factor a (TNFα), interleukin 6 (IL-6), and C-reative protein (CRP). Under inflammatory and oxidative stress conditions, a key transcription factor, NF-kB, is activated. This key pathway in turn activates a proinflammatory cascade including TNFα and IL-6. Both TNFα and NF-kB further inhibit the transcriptional activity of peroxisome proliferator- activated receptor- y (PPARγ) in insulin sensitive cells. PPARγ is a major regulator of lipid metabolism and glucose homeostasis, important in maintaining insulin sensitivity. Genetic variations in PPARγ have been associated with insulin resistance and hyperglycemia in several populations. Thus the activation of the NF-kB pathway and deactivation of PPARγ, due to altered gene expression or genetic variation may lead to modifications in several important metabolic functions in obesity and diabetes.
This proposal is designed to provide preliminary data clarifying mechanisms underlying the chronic inflammation of diabetes and obesity. It has been shown that proinflammatory factors are secreted by the adipose tissue in obesity-linked inflammation. The role of the expression of inflammatory genes in circulating immune cells such as monocytes and lymphocytes in contributing to systemic inflammation and their relationship to whole body insulin resistance is less clear. Biological samples using less invasive techniques are needed to identify markers for obesity and diabetes in at risk populations. Circulating white cells are highly metabolically active, and readily accessible. This proposal will focus therefore on characterizing proinflammatory genes that regulate key pathways that lead to insulin resistance using circulating white blood cells from a well-defined, high risk Hispanic adolescent population in the Lower Rio Grande Valley (LRGV).
The main goals of this proposal are to determine if gene expression differences in key molecules governing inflammation and insulin sensitivity pathways in circulating immune cells are associated with obesity and insulin resistance in Mexican-American adolescents. The supplementary goal is to determine if genetic variations in these biological markers are correlated with differential gene expression. The long-term research plan is to extend these studies investigating risk factors in obesity and T2DM to a prospective, randomly sampled population cohort in the LRGV.
