2017-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/690138摘要：肥胖盛行率在近年急遽升高，並被視為心血管疾病的主要成因。嚴重的肥胖誘發 血液動力學的變化，並進一步引發心臟結構與功能的改變。長時間的病態肥胖，最終 將導致心臟衰竭。 代謝症候群(metabolic syndrome, MetS)與代謝健康型肥胖(metabolically healthy obesity, MHO)是肥胖的兩種表型。MetS 的肥胖個體常伴隨腹部肥胖、胰島素阻抗及血 脂異常，MHO 的個體則無代謝異常的情況發生。然而，MetS 與MHO 的人皆易誘發心 臟衰竭。文獻指出代謝異常，例如脂毒性，是MetS 誘發心臟衰竭的主因。然而，代 謝異常卻不是MHO 導致心臟衰竭的原因，其確切的致病機轉目前仍不清楚。 粒腺體在心臟保護治療上，逐漸成為研究主流。在心臟衰竭產生的初期即可觀察 到粒腺體的功能異常，並隨著心臟衰竭的惡化而持續發生。維持受損心臟粒腺體的生 合成，以及減少粒腺體活性氧化物質的產生，是獲得有效治療最具潛力的兩個方向。 而且，脂肪分佈的部位會影響脂激素分泌的方式，終而改變粒腺體和心臟的功能。 我們先前成功建立MetS 及MHO 迷你豬模型，兩種胖豬皆被診斷出心肌病變。 MetS 豬的心臟並發現粒腺體結構破損，以及心臟外圍包覆大量脂肪。然而，究竟粒腺 體與心包脂肪在肥胖引發心肌壞死中扮演多重要的角色, 特別是MHO 誘發的心肌病 變仍是未知。據此，我們合理推定肥胖、心包脂肪、粒腺體功能及心臟功能之間存在 著某種關連。 本研究目的為 1. 探討Mets 及MHO 迷你豬的左心室粒腺體功能及能量代謝 2. 研究MetS 迷你豬心包脂肪、內臟脂肪及皮下脂肪的特徵 3. 利用功能調控的細胞試驗，研究肥胖誘發心肌病變的分子機制 本研究成果將有助於找到肥胖致病的機轉並發展成臨床治療的可能性。<br> Abstract: The prevalence of obesity is increasing rapidly over the recent decades and has been regarded as a direct cause of cardiovascular diseases. Severe obesity induces hemodynamic alterations and leads to structural and functional changes in the heart. Prolonged severe obesity eventually results in the development of heart failure. Metabolic syndrome (MetS) and metabolically healthy obesity (MHO) are two main phenotypes of obesity populations. Obese individuals with MetS are accompanied with abdominal obesity, insulin resistance and dyslipidemia, whereas MHO individuals are obese without any metabolic dysfunction. Both MetS and MHO are prone to induce heart failure. Literatures point that metabolic dysregulation, such as lipotoxicity is responsible for MetS-induced heart failure, whereas it is not the cause for MHO-induced heart failure. The exact mechanism for MHO-induced heart failure remains unknown. Mitochondria are recently taking the center stage for novel cardioprotective therapies, as their dysfunction appears early and invariable in the development of heart failure. Maintenance of mitochondrial biogenesis against cardiac insults and reduction in mitochondrial reactive oxygen species production are the two promising directions that may soon yield effective treatments. Moreover, the distribution of adipose tissue affects the pattern of adipokine secretion and consequently alters the mitochondrial and heart functions. Our previous study successfully established Mets and MHO minipig models. Both minipigs are diagnosed as cardiomyopathy. In addition, we found a disruption in the structure of mitochondrial membranes and more pericardial fat accumulation in the heart of MetS animals. Whether and to what extent the impairment of mitochondria and pericardial fat contributes to the obesity-induced cardiomyopathy, especially in MHO-induced cardiomyopathy is still unclear. Accordingly, we proposed a link among obesity, mitochondrial functions, pericardial fat, and heart functions. Our specific aims are 1 Study the mitochondrial functions and energy metabolism in the left ventricle of MetS and MHO minipigs 2 Investigate the characteristics of pericardial, visceral and subcutaneous adipose tissue of MetS minipigs 3 Explore the molecular mechanism of obesity-induced cardiomyopathy by a loss-of-function and/or gain-of-function cell model Results of this project would be invaluable in understanding the pathophysiology of obesity-induced cardiomyopathy as well as in developing therapeutic strategies.飲食誘發肥胖代謝症候群代謝健康型肥胖粒線體功能心包脂肪心肌病變dietary-induced obesitymetabolic syndromemetabolically healthy obesitymitochondrial functionpericardial fatcardiomyopathy