Pro-opiomelanocortin（POMC）是一種前軀賀爾蒙，製造包括a-melanocyte-stimulating hormone (a-MSH，β-MSH，γ-MSH)、 corticotropin（ACTH）和b-endorphin（b-EP）等許多具功\\能性的片段，作用在中樞和周邊神經系統。在大腦主要用來控制疼痛、代謝、能量平衡、色素產生、腎上腺功能和脂肪生成。然而系統性POMC基因在代謝方面所造成的病理變化，像是Cushing’s syndrome或者肥胖症的研究較少為人所了解，在此經由adenovirus gene delivery system 攜帶POMC基因誘發C57/BL6小鼠肝臟大量表現POMC來觀察小鼠體內的病理變化；在腎上腺這個負責分泌corticotropin （ACTH）的腺體器官造成直接的破壞力，血清中的ACTH濃度呈現顯著升高且外觀上體積明顯增厚，ACTH接受器melanocortin type 2 receptor（MC2-R）的含量卻大量減少，猜測POMC過度表現使血液中ACTH含量增加但也回頭抑制標的器官。同時檢查胰臟方面的問題試著解釋因Cushing’s syndrome而產生的生理異常，有潛力進展成為第二型糖尿病，利用胰島素和昇糖素抗體標定在胰臟蘭氏小島內發現到hepatic POMC overexpression實驗組的胰島素量明顯減少，而昇糖素的表現並無差別，猜測可能原因是蘭式小島無法有效分泌足夠的胰島素使得血糖控制失衡。透過血清學檢查和肝臟切片發現hepatic POMC overexpression實驗組具有明顯的肝功能異常現象，血清中ALT、AST有意義的升高，肝組織也觀察到大量脂質堆積，評估其肝醣含量也大量銳減不到1/4，這反映出POMC老鼠的肝醣被分解轉變成脂肪囤積在臟器內，印證了POMC gene delivery mediated POMC overexpression 確實會造成老鼠生理極大破壞，內分泌失調與肝功能損傷。

The pro-opiomelanocortin (POMC) prohormone produces several biologically active peptides, including α-melanocyte-stimulating hormones (α-MSH, β-MSH, γ-MSH), corticotrophin (ACTH) and β-endorphin. POMC-expressing neurons in the brain play a major role in the control of pain, energy homeostasis, pigmentation, adrenocortical function, and sebaceous gland lipid production. 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 employed adenovirus gene delivery system to achieve POMC overexpression in the livers of adult C57/BL6 mice. In the endocrine system of adrenal glands, hepatic POMC overexpression mice display hypertrophy the ACTH levels elevated concentrations in the blood, the ACTH receptor, melanocortin type 2 receptor (MC2-R) were decrease. This phenomenon explained the local adrenal gland tissue was inhibiting and feedback from central hypothalamic-pituitary- adrenal axis. Meanwhile, we investigated the islets of Langerhans in hepatic POMC overexpression mice, the insulin were disappear but the glucagon were constant, these reflect the blood sugar were loss of balance, maybe progress to metabolic syndrome. Subsequently, hepatic POMC overexpression resulted in liver injuries that the ALT and AST levels were significantly higher, the fat accumulation in the liver and the glycogen were diminished to nearly 1/4 of basal levels. Evidence the hepatic POMC overexpression induced inflammatory and fatty changes in the livers of mice. In summary, POMC gene delivery induces systemic POMC overexpression and results in fatty liver and adrenal dysfunction, which may facilitates a mice model for Cushing’s-like metabolic syndrome.

Abstract in Chinese 3

Abstract in English 4

Abbreviations 5

Introduction 6

Specific Aims 21

Materials and Methods 22

Results 24

Discussion 31

Figures 37

Appendix 64

References 75

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