探討腎素-血管縮收素系統機制與代謝症候群 (Metabolic Syndrome)的關聯性

Abstract

肥胖 (obesity)是主要的新陳代謝症候群（metabolic syndrome）之一，通常與瘦體素阻抗性 (leptin resistance)及導致胰島素阻抗性 (insulin resistance)有關。然而，如何提高瘦體素的敏感性 (leptin sensitivity) 和改善新陳代謝症候群，目前還沒有明確的藥物與方法。目前已知道經由血管收 縮素受體阻斷劑（angiotensin receptor blockers; ARB）或血管收縮素轉換酶抑制劑（angiotensin converting enzyme inhibitors; ACEI）來抑制腎素-血管收縮素系統（renin angiotensin system; RAS） 可以降低血壓，並提高胰島素的敏感性 (insulin sensitivity)。同時，我們已經證實，缺乏腎素的小 鼠（Ren1c-/- mice）會呈現低血壓，體型偏瘦和提高胰島素敏感性以及胰脂肪酶表現 (decreased pancreatic lipase) 減少的情況，但是Ren1c-/-小鼠的食物攝取 (food intake)以及身體活動 (physical activity)和野生型小鼠(wild type mice)比較並沒有明顯差異。由於Ren1c-/-小鼠如何導致這些表現型 態的作用機制至今尚未完全明瞭。我們的研究目標是想要了解抑制腎素-血管收縮素系統如何導致 Ren1c-/-小鼠的體型偏瘦和提高胰島素敏感以及胰脂肪酶的表現降低的機制。 從我們的觀察和其他實驗室的調查：1) 血管收縮素Ⅱ(angiotensin II)可以誘發並激活 JAK-STAT3-SOCS3 的信號傳遞。JAK-STAT3-SOCS3 的信號與瘦體素阻抗性 (leptin resistance)有著 密切的關係；如果過度激活JAK-STAT3-SOCS3 的信號會引起瘦體素阻抗性並導致肥胖和新陳代謝 症候群。我們給予野生型小鼠血管收縮素受體阻斷劑（angiotensin receptor blockers; ARB）或血管 收縮素轉換酶抑制劑（angiotensin converting enzyme inhibitors; ACEI）兩個星期，發現在脂肪組織 和肝臟中抑制細胞因子信號3（SOCS3）的表現有非常明顯的減少，此情況與Ren1c-/-小鼠極其類 似。這個結果暗示抑制血管收縮素II 可能提高瘦體素的敏感性及改善新陳代謝症候群; 2）雖然 Ren1c-/-小鼠注射血管收縮素II 可增加胰島素阻抗性，但它們的肥胖程度並沒有明顯的增加並且保 持原來的偏瘦體型。這個結果暗示著抑制腎素 (renin)減少肥胖不是經由血管收縮素II 的信號路徑。 3）胰脂肪酶是一種重要的脂肪酶，可以將食物中的脂肪在小腸中分解成游離脂肪酸並在小腸中吸 收。Ren1c-/-小鼠的胰臟具有較低的胰脂肪酶表現並增加糞便中脂肪排泄物，然而，Ren1c-/-小鼠注 射血管收縮素II 後，並沒有明顯改變胰脂肪酶的表現，反而Ren1c-/-小鼠注射腎素 (human renin) 會 增加，並且恢復胰脂肪酶的表現與野生型小鼠相同的程度。這個結果暗示腎素在調節胰脂肪酶的表 現扮演著重要的作用。 因此，本研究的目的是使用Ren1c-/-小鼠去探討腎素-血管收縮素系統和新陳代謝症候群之間 的關聯性與機制，並期望實現下列目標：（1）是否藉由抑制腎素-血管收縮素系統可提高瘦體素的 敏感性。（2）是否腎素可以增加肥胖程度，並且是經由腎素-MAPK 的信號路徑 (Renin-MAPK pathway)。(3）確定Ren1c-/-小鼠偏瘦的體型是否因為缺乏腎素的關係導致胰脂肪酶的表現降低並 造成無法吸收食物中的脂肪，而增加糞便中脂肪排泄物。 我們希望此計畫完成後，能夠找出腎素-血管收縮素系統和新陳代謝症候群之間的關聯性與機 制，並創造出新的治療方法。我們相信此計畫將對肥胖與新陳代謝症候群的治療做出重大的貢獻。

Obesity is a central metabolic syndrome (MS), which is often associated with leptin resistance and leads to insulin resistance. However, how to improve leptin sensitivity and ameliorate MS is still unclear. Inhibition of the renin angiotensin system (RAS) by angiotensin receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI) decreases blood pressure, and improves insulin sensitivity. We have demonstrated that mice lacking renin (Ren1c) have low blood pressure, are lean and insulin sensitive, as well as decreased pancreatic lipase without changes in food intake and physical activity, but its mechanism is not completely understood. The goal of our study is to clarify the mechanisms of how changing RAS causes lean and insulin sensitive phenotype as well as lower pancreatic lipase expression. From our observations and other investigators: 1) Angiotensin II (Ang II) is an activator of JAk-STAT3-SOCS3 signaling pathway, which is associated with leptin resistance. Both wild type mice treated with either ARB or ACEI, and Ren1c-/- mice have decreased suppressor of cytokine signaling 3 (SOCS3) expression in their adipose tissue and the liver, suggesting inhibiting Ang II may improve leptin sensitivity; 2) Although administration of Ang II to the Ren1c-/- mice increases insulin resistance, their adiposity stays low, suggesting inhibiting renin decreases adiposity independent of Ang II; 3) pancreatic lipase is an important enzyme to hydrolyze dietary fat into free fatty acids in the digestive system. Ren1c-/- mice have lower pancreatic lipase as compared to wild type mice; however, administration of Ang II to the Ren1c-/- mice does not restore pancreatic lipase gene expression when human renin corrects it. This suggests that renin plays an important role in the regulation of pancreatic lipase expression. Therefore, the aim of this study is to use Ren1c-/-mice to explore the mechanistic connection RAS and MS, and expect to achieve the follow goals: (1) Determine whether inhibiting RAS improves leptin sensitivity. (2) Determine whether renin increases adiposity independent of Ang II. (3) Determine whether decreased pancreatic lipase plays a pivotal role in dietary fat loss of mice lacking renin through renin effects, which contribute to lean phenotype. Completion of our work will improve our understanding of the role of RAS in obesity and MS, and contribute to the development of novel treatments capable of attenuating the process of MS.