| 摘要: | 青少年肥胖症在過去三十年來是一個愈來愈嚴重的公共衛生問題。不少青少年年紀輕輕就罹患糖尿病更被歸咎為肥胖症盛行的後遺症。除了飲食習慣與生活型態等危險因子，代謝途徑的異常與肥胖基因的表現被認為是造成青少年肥胖的兩大重要因素。Growth arrest-specific 6 (Gas6)是一種維他命Ｋ依賴的蛋白質，可被人體脂肪細胞所分泌。過去一些細胞或動物實驗發現，Gas6和它的Axl 受體可能與脂肪堆積、肥胖相關發炎、胰島素阻抗產生有關。然而直到今日，我們還不清楚Gas6/Axl系統對青少年肥胖的臨床重要性。因此我們設計了兩個臨床實驗去探討血中Gas6/sAxl蛋白質以及GAS6/AXL基因多型性於青少年身體脂肪組成、全身發炎反應及胰島素阻抗中扮演之角色。
我們的研究發現青少年血中Gas6蛋白質濃度與身體質量指數、腰圍、腰臀比、身體脂肪含量以及發炎細胞激素(C-反應蛋白、腫瘤壞死因子-α)成高度正相關。對於體重過重與肥胖的青少年，每增加血中1 ng/mL Gas6蛋白質濃度，便會增加15–19%導致全身胰島素阻抗的風險。此外，3個單核苷酸多型性GAS6 rs8191974、AXL rs2304232和 AXL rs4802113與男性青少年的身體脂肪、發炎細胞激素和胰島素阻抗狀態有關。尤其是同時帶有GAS6 rs8191973的GG 基因型和GAS6 rs8191974的GG基因型的男性青少年將有較高的風險導致肥胖症與高度全身性發炎反應的出現。綜合我們的臨床研究結果與過去細胞、動物實驗發現，Gas6/Axl系統對於青少年肥胖與相關併發症的出現扮演非常重要的角色，或許調控Gas6/Axl系統的活性將成為未來另一種控制青少年肥胖症的治療方式。
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. |
