肥胖及其相關代謝性症候群包含糖尿病、高血壓、心血管疾病甚至癌症的發展對於現今社會中帶來龐大的健康、經濟負擔。其中異常、不健康的脂肪細胞的擴張與肥胖的發展息息相關，脂肪細胞擴張主要包含兩個步驟: 新生脂肪細胞的分化、成熟脂肪細胞的肥大。TG-interacting factor 1 (TGIF1)在先前研究報導被指出在小鼠前驅脂肪細胞或是人類脂肪源幹細胞的分化中具有必須的角色，此外，在高油脂飲食誘導肥胖的老鼠模型脂肪組織GEO dataset中，也能觀察到脂肪組織中tgif1 mRNA表達的上升。雖然在上述研究中發現TGIF1在脂肪細胞中佔有重要的角色，但詳細機制至今仍尚未釐清。因此在本研究中，我們首先驗證在高油脂飲食誘導肥胖的老鼠模型脂肪進行組織中觀察到TGIF1蛋白質及mRNA表現量證實有明顯增加之現象，並進一步利用TGIF1過度表達或剔除的3T3-F442A前驅脂肪細胞株並發現TGIF1在脂肪細胞分化早期中具有重要的角色，且主要透過Insulin/ERK路徑來磷酸化TGIF1 蛋白質Threonine 235及239位點增加其蛋白質穩定性，並於脂肪細胞分化早期透過活化C/EBPβ promoter、藉由PPARγ response element抑制p27kip1表現、促進cell cycle的進程來參與在脂肪細胞分化過程中的mitotic clonal expansion，進而加強脂肪細胞的分化。因此，希望透過了解此脂肪細胞分化機制在未來能夠提供在肥胖相關疾病治療中的一個治療標的。

Obesity and its related metabolic syndromes, including diabetes, hypertension, cardiovascular diseases, and even cancers, bring significant health and economic burdens on modern society. The abnormal and unhealthy adipocytes expansion is closely associated with obesity, involving two main steps in adipocyte expansion: the differentiation of newly formed adipocytes and the hypertrophy of mature adipocytes. Previous studies have highlighted the essential roles of TG-interacting factor 1 (TGIF1) in the differentiation of murine preadipocytes or human adipose-derived stem cells. Additionally, an increase in tgif1 mRNA expression has been observed in adipose tissue from mouse models of high-fat diet-induced obesity GEO datasets. Although the importance of TGIF1 in adipocytes has been recognized in these studies, the detailed mechanisms remain unclear. Therefore, in our present study, we validated a significant increase in protein and mRNA expression of TGIF1 in adipose tissue from mouse models of high-fat diet-induced obesity. Subsequently, we employed 3T3-F442A preadipocytes with overexpression or knockout of TGIF1 and revealed its crucial roles in the early stages of adipocyte differentiation. This process is primarily mediated by insulin/ERK pathway-induced phosphorylation of TGIF1 protein at threonine 235 and 239, which enhance its protein stability. Furthermore, TGIF1 participates in mitotic clonal expansion by activating the C/EBPβ promoter, suppressing p27kip1 expression through PPARγ response elements, and promoting cell cycle progression, thereby enhancing adipocyte differentiation. Therefore, modulating TGIF1 expression in adipocytes may provide promising therapeutic targets for obesity-related diseases.

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