在第二型糖尿病的患者與肥胖的人群中，好發高血脂症的機率較高以及血液會有較高的血清素濃度。根據研究指出，血液中過多的游離脂肪酸會導致胰島素抗性的增加並損壞胰臟beta細胞之功能。近年的文獻顯示，在db/db肥胖小鼠的胰臟beta細胞，血清素受器2C的表現量是上升的並且影響了胰島素的分泌。然而，游離脂肪酸改變了血清素受器2C並進而影響胰島素分泌的詳細機制還尚未明確。因此本篇的主要目的為探討游離脂肪酸對於血清素受器2C的影響以及血清素受器2C的訊息傳導在胰臟beta細胞胰島素分泌時所扮演的角色。在本研究中，我們首先利用20週的高脂飲食餵食小鼠，在屆滿20週時測量血液生化值，發現高脂飲食組除了體重上升外，更有葡萄糖耐受不良及胰島素敏感性下降的情形，這確定了我們成功地誘發小鼠產生肥胖及胰島素阻抗。接著我們將小鼠的胰臟做切片並染色，發現血清素受器2C的表現量上升。為了更進一步探討其詳細的機制，我們將老鼠beta細胞株MIN6處理棕櫚酸後，發現胰島素的分泌上升了，血清素受器2C的表現量也是上升的。Gαq/11蛋白為血清素受器2C訊息傳導之下游，其表現量也經處理棕櫚酸後而上升。此外，鈣離子的恆定對於胰島素釋放也相當重要，因此我們利用單細胞離子影像分析系統，發現處理棕櫚酸後，細胞內鈣離子明顯上升。為了確定棕櫚酸是透過血清素受器2C影響鈣離子的恆定，因此我們加入血清素受器2C拮抗劑SB242084，發現細胞內鈣離子下降了。綜合上述的結果，我們認為棕櫚酸使胰島素分泌增加是透過增加血清素受器2C的表現及活化其下游鈣離子訊息傳遞路徑所導致。

Patients with type 2 diabetes mellitus (T2DM) and obesity usually have high plasma levels of serotonin (5-hydroxytryptamine; 5-HT) and hyperlipidemia. It has been reported that excess free fatty acids (FFAs) may increase the insulin resistance and lead to pancreatic beta cell dysfunctions. Recent study showed that increased expression of serotonin receptor 2C (5-HT2CR) affected insulin secretion in pancreatic islets of db/db mice. However, the underlying mechanism(s) how FFAs alter insulin secretion via 5-HT2CR signaling are not fully understood. In this study, we aimed to investigate the effects of FFAs on 5-HT2CR and dissect the role of 5-HT2CR signaling on insulin secretion in pancreatic beta cells. In our study, we fed C57BL/6 mice with high-fat diet (HFD) or standard chow for 20 weeks. We found that mice fed with HFD showed obesity, glucose intolerance and lower insulin sensitivity compare with mice fed with standard chow, suggesting that our mice were obesity and became insulin resistance. Furthermore, we found that 5-HT2cR expression was increased in pancreatic islets of mice fed with HFD. Additionally, we found that palmitic acid (PA) treatment increased the glucose-stimulated insulin secretion (GSIS) and the expression of 5-HT2CR in MIN6 beta cells. The expression of Gαq/11 also increased in MIN6 beta cells incubated with PA. Calcium signaling is essential for insulin release. We found that PA increased ER calcium release and SOCE activity. To investigate whether PA affect ER calcium release and SOCE through 5-HT2cR signaling pathway, we used 5-HT2CR antagonist SB242084 to treat MIN6 beta cells, and found that ER calcium release and SOCE were decreased. Taken together, our results suggested that PA increased insulin secretion through up-regulated 5-HT2CR expression and activated downstream calcium signaling pathway.

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