Pro-opiomelanocortin (POMC)是一個由241個胺基酸多肽鏈組成的前軀物，經過轉譯修飾後產生一系列具有不同生物活性的小片段胜肽，包括 α-, β -, γ-melanocyte-stimulating hormone (α-MSH, β-MSH, γ-MSH )，β-endorphin (β-EP) and adrenocorticotrophic hormone (ACTH)。POMC 衍生胜肽在食慾及能量衡定中皆扮演了重要的角色。近年來，系統性 POMC在代謝方面所造成的病理變化，如：庫欣氏症 (Cushing’s syndrome) 及肥胖症正在積極的研究調查。在本研究中，我們利用基因傳送系統攜帶POMC基因誘發C57/BL6小鼠獲得系統性POMC過度表現來觀察小鼠體內生理變化。我們採集小鼠血清進行血液生化分析並收集腹部內臟脂肪組織秤重分析。在研究結果中我們發現，POMC過度表現並無造成小鼠食量及體重的增加。這個結果顯示，經由POMC基因傳送會誘發小鼠內臟脂肪堆積以及體內新陳代謝改變。同時，我們也觀察到系統性POMC過度表現造成小鼠血液中三酸甘油脂及總膽固醇濃度顯著上升。然而，在POMC基因傳送後的第一週到第四週，小鼠血漿中葡萄糖濃度皆上升而且在第四週時甚至出現葡萄糖耐受性異常症狀。同時，我們發現，胰島素阻抗性症狀卻早在POMC基因傳送後的第一週即出現。除此之外，Micro-CT掃描與組織型態學研究證實，與實驗組小鼠比較後發現，在POMC過度表現的小鼠身上內臟脂肪有顯著增加。這些數據顯示，POMC基因傳送造成系統性ACTH濃度上升及胰島素阻抗性症狀產生。這些現象與臨床上庫欣氏症的個體發生特點相似。總結以上所述，POMC基因傳送誘發系統性POMC過度表現並且造成內臟脂肪堆積與胰島素阻抗性的產生；這些結果提供我們能更方便建立一個類庫欣氏症代謝症候群 (Cushing’s-like metabolic syndrome)的小鼠實驗模式。

Proopiomelanocortin (POMC) is a polypeptide precursor with 241 amino acid residues which undergoes extensive post-translational modification to yield a range of smaller, biological active peptides including α-, β -, γ-melanocyte-stimulating hormone (α-MSH, β-MSH, γ-MSH )，β-endorphin (β-EP) and adrenocorticotrophic hormone (ACTH). POMC-derived peptides play important roles in appetite and energy homeostasis. Recently, the peripheral POMC system is under active investigation to delineate their pathogenic roles in metabolic diseases such as Cushing’s syndrome and obesity. In the present study, we utilized adenovirus gene delivery system to achieve systemic POMC overexpression in adult C57/BL6 mice for at least 30 days. Subsequently, the plasma and abdominal adipose tissue of mice were collected and analyzed by biochemical assays and weight determination respectively. POMC overexpression did not increase in the food uptake and body weight. These results imply that local POMC gene delivery induced the visceral fat accumulation and altered the metabolism in mice. It was observed that systemic POMC overexpression significantly elevated the triglyceride and the cholesterol levels in mice. However, POMC gene delivery also induced elevated plasma glucose concentration at weeks 1-4 and evoked glucose tolerance in mice at week 4. Interestingly, insulin resistance was readily detected in POMC-transduced in mice at as early as week 1. Besides, Micro-CT scanning and histological studies demonstrated that the visceral fat was significantly increased in POMC over-expressing mice compared with control animals. These data indicate that hepatic POMC gene delivery causes systemic ACTH rise and insulin resistance, which recapitulates the clinical features of Cushing’s syndrome. In summary, POMC gene delivery induces systemic POMC overexpression and results in visceral fat accumulation and insulin resistance, which may facilitates a mice model for Cushing’s-like metabolic syndrome.

CONTENTS
Page
Abstract in Chinese 6
Abstract in English 7
Abbreviations 9
Introduction 10
Specific Aims 19
Materials and Methods 20
Results 24
Discussion 28
Figures 36
Supplemental Figures 44
Appendix 49
References 58

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