Investigation of the role of growth arrest-specific 6 in obesity, obesity-associated inflammation, and systemic insulin resistance among adolescents

• Main Authors: Fone-Ching Hsiao, 蕭峯青
• Other Authors: 林裕峯
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/87811252127247142512

博士 === 臺北醫學大學 === 臨床醫學研究所 === 102 === 　　Childhood obesity is a serious and growing public health problem that has arisen over the past three decades. The increasing occurrence of disorders such as type 2 diabetes during childhood is believed to be a consequence of this obesity epidemic. In addition to several behavioral and dietary risk factors, metabolic pathway disturbance and genetic predisposition are both the important factors in the pathogenesis of childhood obesity. Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Several preclinical studies indicate that Gas6 and its　receptor tyrosine kinase of Axl may be involved in the pathogenesis of obesity and its complications, including systemic inflammation and insulin resistance. However, until now, little has been known the clinical significance of the Gas6/Axl system in childhood obesity. Therefore, our studies were designed to (1) determine the relationship between circulating Gas6 and sAxl proteins, childhood obesity, obesity-associated inflammation, and insulin resistance status (Study I); (2)　explore the effects of GAS6 and AXL gene polymorphisms on adiposity, systemic inflammation, and insulin resistance among Taiwanese adolescents (Study II).　 After multistage sampling from the data of the Taipei Children Heart Study-III, we collected 832 adolescents for analyses of Study I, and 727 adolescents in the final analyses of Study II. In Study I, we found that circulating Gas6 levels were significantly positively correlated with body mass index (BMI) Z-score, waist circumference (WC), waist/hip circumference ratio, body fat mass, serum high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-α levels among overweight and obese adolescents.　In addition, every 1 ng/mL increase in circulating Gas6 concentration corresponded to a 15–19% increase in the risk of developing insulin resistance among overweight and obese adolescents. In Study II, we found that 3 SNPs of GAS6 rs8191974, AXL rs2304232, and AXL rs4802113 were strongly associated with adiposity, inflammatory cytokines, and insulin resistance status among boys. Boys with both the GG genotype of GAS6 rs8191973 and the GG genotype of GAS6 rs8191974 exhibited higher BMI, WC, IL-6, and hsCRP levels than the boys carrying both the C allele of the GAS6 rs8191973 and the A allele of the GAS6 rs8191974. In conclusion, these results together with those from studies in cellular and animal models, encourage the study of the Gas6/Axl system in childhood obesity and its potential complications, and further support the hypothesis that modulation of Gas6 activity may indeed provide an important intervention point for future therapies.