利用飲食誘導肥胖迷你豬模型探討心包油之特徵及其與心房震顫之關聯

Abstract

脂肪在代謝的過程中扮演著重要的角色，而過多的脂肪堆積常導致代謝疾病的發生，目前已有相關研究指出，內臟脂肪 (Visceral fat, VF) 的多寡與第二型糖尿病、胰島素阻抗等疾病皆有顯著的正相關，心周圍脂肪 (Pericardial fat, PF) 為包覆在心臟外圍的脂肪，亦有文獻指出心周圍脂肪生成的面積大小與心臟相關疾病的發生率呈現正相關。目前常用的實驗動物大致可分為兩大類：一、齧齒類動物，二、哺乳類大型動物如豬等，但是由常用的動物模型並無法觀察到大量心周圍脂肪的堆積。因此本論文的目標是建立飼料誘導的肥胖迷你豬模型，並探討其心功能和脂肪細胞的特徵。 本試驗使用十九頭起始月齡約為四個月的李宋豬作為實驗動物，取得之豬隻隨機分為兩組，一組為餵飼西方飼糧 (Western diet, W) (四公五母)，而另外一組則為餵飼一般飼糧 (Control diet, C) (五公五母)，實驗為期5個月，犧牲後取其右心房以及脂肪組織進行分析實驗結果顯示，W組豬隻體重和背脂厚度皆顯著高於C組。在血液生化值部分，W組不僅有較高的葡萄糖、三酸甘油脂、和總膽固醇濃度，還出現葡萄糖不耐的情況，檢測其血液中發炎因子亦發現W組別有較高的TNF-α濃度。從心臟電生理的結果顯示，W組別有右心房震顫的問題，進一步分析右心房和右心室的特徵，結果顯示，比起C組別，不管是在右心房還是右心室，W組別皆含有較高的三酸甘油濃度、較多的活性氧物質 (ROS) 及較差的抗氧化能力。 比較兩組別心周圍脂肪之重量，結果顯示W組別的PF重量顯著高於C組別。與C組別相比，W組別的PF有較好的抗氧化能力，相反的，VF的結果則顯示W組別抗氧化能力顯著低於C組別。而ROS的部分僅有W組PF有較高的趨勢 (p = 0.064)。在脂肪組成分分析中顯示，W組別中不論是PF或是VF，其多不飽和脂肪酸皆顯著低於C組別，尤其是在n6不飽和脂肪酸的部分，W組別亦顯著低於C組。對W組別脂肪組織產生的發炎因子進行檢測，結果顯示每單位的PF比起VF有較高的TNF-α和IL-6濃度。 綜合以上結果，經長期西方飼糧誘導後，李宋豬會產生肥胖以及代謝異常的情況，右心房/室的抗氧化能力下降，且堆積大量的TG，PF會分泌較多的發炎因子，可能導致右心功能的下降。本實驗的結果顯示李宋豬飼料誘導肥胖模型具有成為生醫用實驗動物平台的潛力，在未來不管是用於對心房震顫的治療，或是對心周圍脂肪更近一步的研究，李宋豬皆是極佳的研究介質。

Adipose tissue plays an important role in metabolic regulation, however, surplus adipose tissues cause metabolic dysfunction. Excess visceral fat (VF) contributes to the pathogenesis of metabolic-related diseases, such as type II diabetes, fatty liver, and cardiovascular diseases (CVDs); while pericardial fat (PF) is highly associated with the progression of CVDs, thus attracting more attention recently. The objective of this study was to setup a dietary induced obese (DIO) mininpig model, the heart function and the characteristics of adipose tissues (visceral and pericardial) were analyzed to elucidate their role in metabolic regulation of DIO pigs. Four-month-old Lee-Sung minipigs were randomly assigned to two groups: control diet (C, 5 castrated males, 5 female) and Western diet (W, 4 castrated males, 5 female), for a 5-month experimental period. Minipigs were sacrificed, the right cardiac tissue and the adipose tissues (VF and PF) were isolated for analysis in the end of experiment. W pigs gained more body weight and habited more back fat. Comparing with C group, W pigs had higher plasma levels of glucose, triglycerides (TG), total cholesterol and TNF-α. Beside, glucose intolerance were developed in the W pigs, indicating that the Western diet induced metabolic dysfunction in W pigs successfully. The incidence of atrial fibrillation is higher in W pigs. In W pigs, reactive oxygen species (ROS) and TG were higher in the right cardiac tissue than C pigs. In addition, the oxygen radical absorption capacity (ORAC) was higher in the right atrium and ventricle in C pigs. Compared with C pigs, W pigs had heavier PF weight. Higher ORAC was found in the PF of W pigs; in contrast, W pigs exhibited a lower ORAC in the VF then the C pigs. In PF, W pigs exhibited more ROS than C pigs (p = 0.064). The result of fatty acid composition shown that less polyunsaturated fatty acids, especially n6 PUFA in the PF of W pigs. A greater protein expression of TNF-α and IL-6 were observed in the PF of W pigs. In summary, western diet induced obesity and metabolic disorders in Lee-Sung pigs. Worse anti-oxidation ability and more TG were found in RV/RA of W pigs. Higher inflammation was induced in the PF of W pigs, which might contribute to the dysfunction in the right cardiac tissue. Our results implied that dietary induced obesity Lee-Sung pigs could be a potential model for studying pericardial fat and obesity-related atrial fibrillation.