FAP-1透過調節血糖影響小鼠體重的機制研究

Abstract

FAP-1為蛋白質酪氨酸磷酸酶家族中的一員，除了能抑制由Fas刺激產生的細胞凋亡，也有研究指出FAP-1可能與抑制腫瘤生長相關。本實驗室先前從荷蘭Dr. Wiljan Hendriks實驗室引進將體內FAP-1具酵素活性的PTP domain剔除 (FAP-1ΔP/ΔP) 的小鼠，經長時間追蹤，發現FAP-1ΔP/ΔP小鼠較Wild-type小鼠體重有顯著的增加。經解剖和組織染色的分析結果指出FAP-1ΔP/ΔP小鼠有較重的白色脂肪，並有脂肪細胞肥大的情形。進一步檢測其進食量和血液生化指標，發現FAP-1ΔP/ΔP小鼠有較高的空腹血糖。為瞭解FAP-1ΔP/ΔP小鼠體內的葡萄糖代謝狀況，我們也同時測量小鼠的空腹胰島素，發現即便FAP-1△P/△P小鼠有較高的空腹血糖，其胰島素數值仍然與野生型小鼠無顯著區別；且經由管餵葡萄糖的葡萄糖耐受性實驗也指出FAP-1ΔP/ΔP小鼠的胰島素釋放量較低。由於經管餵攝入的葡萄糖會透過腸細胞分泌的腸泌素GLP-1引發胰臟β細胞釋放胰島素，因此進一步測量血清中GLP-1的變化，結果指出FAP-1ΔP/ΔP小鼠經管餵葡萄糖仍會分泌GLP-1。進一步以尾靜脈同時注射GLP-1和葡萄糖，發現FAP-1△P/△P小鼠在GLP-1刺激之下無法成功引發胰島素釋放。 根據上述實驗結果，我們因此提出FAP-1可能藉由調控胰臟β細胞中胰島素之釋放，影響小鼠之葡萄糖代謝，導致體重及脂肪增加之表型。由於過去研究指出GLP-1主要會幫助第一階段胰島素的釋放，其中細胞骨架扮演非常重要的角色，因此未來將著重於FAP-1對於胰臟β細胞中細胞骨架的影響進行研究。

FAP-1 is a member of the protein tyrosine phosphatase family, which acts as an inhibitor of Fas-mediated apoptosis. Based on the cell culture based assay, several studies have also indicated FAP-1 to be associated with the inhibition of tumor growth, which still awaits to be validated in vivo. Aiming to study physiological function of FAP-1 in vivo, our lab has delivered a FAP-1 phosphatase-deficient (FAP-1ΔP/ΔP) mouse model from Dr. Wiljan Hendriks’ group. After long-term follow up, we found that FAP-1ΔP/ ΔP mice have significantly higher body weight compared to the wild-type mice, which could be attributed by the hypertrophic adipocytes. Further blood analysis revealed that FAP-1ΔP/ΔP mice have higher fasting blood glucose but equivalent fasting insulin level compared with wild type mice. It suggested a defect of insulin secretion in response to the elevated blood glucose in the FAP-1ΔP/ΔP mice, which indeed has been validated by the oral glucose tolerance test. This study aims to study a possibility that the GLP-1, an incretin hormone released in response to oral glucose gavage to stimulate the secretion of insulin from pancreatic β cells, and its downstream pathway could be defective in FAP-1ΔP/ΔP mice. The GLP-1 level in blood after oral glucose gavage remained normal in the FAP-1ΔP/ΔP mice; however the secretion of insulin after injection of GLP-1 is significantly decreased in the FAP-1△P/△P mice. The results proposed that FAP-1 may function to regulate the secretion of insulin from β cells in response to GLP-1 stimulation, as a mechanism for the increased body weight in FAP-1ΔP/ΔP mice. As documented, GLP-1 mainly induces the first phase of insulin secretion, in which the cytoskeleton plays a very important role. Our ongoing study is thus focused on the function of FAP-1 in regulating the cytoskeleton changes in response to GLP-1 stimulation in primary β cells and in cell culture based assays. Hopefully, the results will help clarify the physiological function of FAP-1 in regulating the glucose metabolism.