| 摘要: | 研究期間：10108~10207;Green tea epigallocatechin gallate (EGCG) and suppressor of cytokine signaling (SOCS)-3 were respectively found to regulate cancer, diabetes, inflammation, hormone signaling, cytokine signaling, and cell growth. In fat cells, EGCG and SOCS-3 were also found to regulate insulin, IGF signaling, and adipokine signaling, as well as energy metabolism. Thus, EGCG and SOCS-3 are important in the fields of biology. Previously we have reported that EGCG reduced the body weight in normal (abnormal leptin receptor) and obese (intact leptin receptor) rats, body fats, adipose tissues mass, and serum lipids, insulin, IGF-I, and leptin. In supporting the anti-obese effect of EGCG, our previous NSC projects indicated that 1) EGCG inhibited preadipocyte mitogenesis through ERK and CDK2 pathways, 2) EGCG suppressed adipogenic differentiation through reduced levels of adipogenesis-controlling factors, such as C/EBPand PPAR, 3) EGCG induced preadipocyte apoptosis through suppression of CDK2 activity and activation of caspase-3 activity, 4) EGCG altered endocrine activity, such as resistin, in adipocytes, 5) an EGCG receptor called 67-kDa laminin receptor (67LR) was identified in fat cells and it mediated anti-insulin and anti-IGF signaling of EGCG in preadipocyte mitogenesis, and 6) EGCG suppressed insulin- and IGF-stimulated adipocyte glucose uptake through the 67LR and AMPK pathways. These findings suggest that EGCG regulates growth, differentiation, endocrine activity, and metabolism in fat cells. The findings of our preliminary reports indicated that EGCG regulate growth, apoptosis, differentiation, endocrine activity, and metabolism in fat cells, as well as could modulate the signaling and expression of SOCS-3-stimulating hormones and adipokines, such as insulin, insulin-like growth factors, leptin, and resistin. Our recent data also observed that EGCG alone inhibited SOCS-3 mRNA expression; in the presence of either insulin, resistin, or endotheline-1, it suppressed insulin-, resistin-, and endothelin-1-stimulated SOCS-3 mRNA expression. This raises possibilities that EGCG signaling may have a direct effect on SOCS-3 production and that SOCS-3 may act as a signaling molecule for EGCG to control mitogenesis, differentiation and metabolism in fat cells. To extend our findings for actions of EGCG on SOCS-3 gene expression and to further understand EGCG modulations of fat cell activities, the overall objective of our 3-year project is to understand the mechanism of how EGCG signaling molecules (e.g., 67LR, AMPK, MEK1/ERK MAPK, JAK/STAT, and PI3K/AKT) regulate the expression of SOCS-3 gene in fat cells during the processes of growth, differentiation, and metabolism, as well as demonstrating a role of SOCS-3 in the EGCG regulation of these processes. In the first year, we will understand the mechanism of how EGCG signaling modulates SOCS-3 and other SOCS gene expression during growth of preadipocytes and demonstrate a role of SOCS-3 in EGCG-inhibited preadipocyte growth. In the second year, we will understand the mechanism of how EGCG signaling modulates SOCS-3 and other SOCS gene expression during the period of fat cell differentiation and demonstrate a role of SOCS-3 in the EGCG-mediated preadipocyte differentiation. In the third year, we will understand the mechanism of how EGCG signaling regulates SOCS-3 and other SOCS gene expression in adipocytes and demonstrate a role of SOCS-3 in EGCG-regulated insulin signaling, IGF signaling, lipid metabolism, and glucose uptake in adipocytes. Thus, the results of this study will provide us with important new insights into the mechanisms of how EGCG signaling regulates SOCS-3 and other SOCS expressions, as well as will demonstrate a role of SOCS-3 in EGCG-modulated hormone and adipokine signaling, growth, differentiation, metabolism, and endocrine activity in fat cells. As EGCG functions to regulate the body weight, obesity, and fat cell activites, the mechanistic results of this study would help explain the mechanism by which EGCG modulates IGF-mediated fat functions and obesity, as well as may possibly be utilized in the treatment and prevention of obesity and obesity-related diseases using green tea or other EGCG-based folk medicines. |
