| 摘要: | 肥胖是一種常見的疾病，與癌症，糖尿病，高血壓以及心血管疾病都有相關。造成肥胖的原因是脂肪細胞數目的增加，或脂肪細胞內三酸甘油酯的堆積。根據研究指出，內分泌與營養都會影響到肥胖的調節作用，其中胰島素在細胞分化時期會刺激細胞進行增生和adipogenesis，並促使細胞進行脂肪生成和抑制脂肪分解作用。然而綠茶唲茶素(亦稱維生素P)，尤其是綠茶表沒食子酸酯型唲茶素酸酯(英文名稱和簡稱分別為 (-)-epigallocatechin gallate和EGCG)，已被證實可以抑制脂肪細胞的增生與分化，並可促使前脂肪細胞和脂肪細胞的apoptosis，所以可作為預防肥胖的保健物質。因此，EGCG是否可調節胰島素刺激前脂肪細胞的增生仍然不清楚。在本論文中，使用3T3-L1前脂肪細胞株做為研究素材，我發現胰島素濃度100 nM，胰島素可分別增加胰島素接受器、IRS1、IRS2、IRS3、Raf1、MEK和 Erk蛋白的磷酸化，但減少IRS-4蛋白的磷酸化，然而前處理EGCG (20μM)於前脂肪細胞可以明顯抑制胰島素所促進訊息蛋白的磷酸化及胰島素接受器與IRS-1和IRS-2兩者之間的結合作用，並且可以明顯抑制胰島素所促進IRS 蛋白質和下游訊息蛋白質之間的結合作用。此外，前處理層粘連蛋白接受器的抗體(67-kDa laminin receptor；被認為是一種EGCG 接受器)，可以中和EGCG抑制胰島素所促進訊息蛋白MEK和 IRS2的磷酸化。以上種種的跡象顯示，EGCG可透過阻礙胰島素的訊息傳導路徑而抑制前脂肪細胞的增生，並且EGCG 可透過層粘連蛋白接受器干擾胰島素的訊息傳導作用。此外，EGCG 比其他綠茶唲茶素干擾胰島素刺激增生更有效果。此篇研究結果可以說明在前脂肪細胞中，EGCG 調節胰島素訊息的作用機制。 Obesity is a common disease, and it was associated with risk of cancer, diabetes, hypertention, and cardiovascular disease. Development of obesity results from increases in the cell number and fat accumulation of adipocyts, and is regulated by endocrine and nutritional factors. Insulin regulates mitogenesis and adipogenesis of fat cells and stimulates lipogenesis and inhibits lipolysis. By contrast, green tea catechins (once called vitamin P), especially (-)-epigallocatechin gallate (EGCG), inhibits proliferation and differentiation of fat cells and induces the apoptosis of preadipocytes and adipocytes. EGCG has been proposed as a chemopreventative for obesity and diabetes. However, relatively little is known about the mechanism of the action of EGCG on insulin-stimulated fat cell function. This study was designed to investigate the pathways of EGCG's modulation of the insulin-stimulated mitogenesis of 3T3-L1 preadipocytes. EGCG decreased insulin-induced increases in levels of phospho-insulin receptor (pIR), phospho-insulin receptor substrates 1, 2, and 3 (pIRS1, 2, and 3), phospho-Raf1, phospho-MEK1/2, and phospho-Erk1/2 proteins and induced further insulin-decreased pIRS4 level. In addition, EGCG reduced the insulin-stimulated associations of IR with IRS1 and IRS2. EGCG also reduced the association of IRS proteins with downstream signaling proteins. Besides, pretreatment with 67-kDa laminin receptor could antagonize the effect of EGCG on insulin-induced pMEK1/2 and pIRS2. These data suggest that EGCG exerts its antimitogenic effects via inhibiting insulin signaling by the 67-kDa laminin receptor-dependent pathway. Moreover, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in changing the insulin-stimulated mitogenic signals. Results of this study may relate to the mechanism by which EGCG modulates insulin-related preadipocytes. |
