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https://nccur.lib.nccu.edu.tw/handle/140.119/157165
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| Title: | IFITM 基因剔除鼠中過度攝食行為之細胞分子機制之研究
Study of the Cellular and Molecular Basis of Hyperphagia in IFITMmdel Mutant Mice |
| Authors: | 陳紹寬 |
| Contributors: | 神科所 |
| Keywords: | 肥胖;焦慮;憂鬱;下視丘;發炎
IFITM;hyperphagia;anxiety;depression;hypothalamus;inflammation |
| Date: | 2017-03 |
| Issue Date: | 2025-05-29 11:56:58 (UTC+8) |
| Abstract: | 過度攝食是由神經內分泌系統調控異常所引起的食慾異常增加所造成，此種異常行為會破壞體內正常的能量平衡，引起糖尿病等代謝疾病，在現代的生活形態中已是健康的一大威脅。在人類與小鼠中下視丘的弓形核與腹內側核是攝食行為的神經調控中樞，其活動會受荷爾蒙，神經胜肽及其他信息分子的調控，然而此調控機制尚未完全清楚。Ifitm 基因是一群序列相似的可被干擾素刺激表現的基因，將這些基因敲除後小鼠會產生過度攝食的行為並會造成肥胖，並最終會造成如瘦素或胰島素阻抗等在糖尿病患者中常見的症狀，因此此種基因敲除鼠可成為研究過度攝食行為的模式動物，同時也可應用於肥胖及糖尿病的研究。在對Ifitm 基因敲除小鼠中醣類的代謝與其血液中周邊調控攝食行為的荷爾蒙(包括瘦素及胰島素)分析結果表明此基因敲除小鼠的過度攝食並非因代謝過快或荷爾蒙分泌不足所引起，可能是由於中樞攝食調控神經網路的黑皮質素訊息傳遞缺失所造成。在檢驗下視丘調控黑皮質素訊息傳遞主要的神經胜肽，包括POMC 及NPY 的表現量時，發現黑皮質素的前驅物POMC 的表現量顯著降低。由於前人研究中表明POMC 敲除鼠會產生過度攝食及肥胖的表現型，與Ifitm 基因敲除小鼠的表現型相似，因此POMC 表現量下降很可能即為Ifitm 基因敲除小鼠過度攝食行為的原因。由於干擾素或Ifitm 基因如何調控攝食行為尚不清楚，本計畫的主要目標即為研究Ifitm 基因缺失造成POMC 表現降低及過度攝食行為之細胞及分子機制。我們的假說為Ifitm 基因缺失可能造成分泌POMC 的神經細胞功能缺失導致無法對瘦素的刺激正常反應，調控Ifitm 基因表現的干擾素也可能參與對攝食行為的調控。本計畫將先確認Ifitm 基因敲除鼠中POMC 表現量下降是否因POMC 的神經細胞功能缺失所造成，同時測試此突變鼠的瘦素訊息傳導途徑是否無法正常運作，最後我們會檢驗是否干擾素會參與攝食行為的調控。本研究將可增加我們對攝食行為調控的了解，並可能發現對攝食行為調控新的調控路徑，從而開發對過度飲食新的調控方式。
Hyperphagia are caused by dysregulation of feeding behavior-controlling neuroendocrine network and often related to metabolic disorders such as diabetes. This aberrant behavior interrupts normal energy homeostasis and has become an increasingly serious threat to public health in modern life style. In both human and mice, feeding behavior is controlled by a complex neuroendocrine system centered by hypothalamic nuclei, including arcuate nucleus and ventromedial nucleus, whose activities are positively or negatively regulated by hormones, neuropeptides, and other signaling molecules such as cytokines. However, detailed molecular mechanisms of this regulatory system are not fully understood. Ifitm genes are a group of interferon-inducible genes. IfitmDel mutant mice with 6 of 7 Ifitm genes deleted exhibit hyperphagia and obesity developed with age. As the obesity developed, these mutants also revealed diabetic like symptoms, including leptin resistance and insulin resistance. The outcome of glucose metabolism and peripheral hormone levels related to eating behavior control indicated that this excessive eating behavior is not due to increased metabolic rate or decreased negative regulatory hormones. Moreover, the levels of pro-opiomelanocortin in hypothalamus are significantly reduced, suggesting that the hyperphagia phenotype of IfitmDel mutants is likely caused by defective central melanocortin signaling. In this proposal, we aim to investigate the cellular and molecular basis of this abnormal feeding behavior. We hypothesize that interferons are involved in food intake inhibition through the function of IFITM proteins on leptin signaling in pro-opiomelanocortin neurons. The mechanisms underlying pro-opiomelanocortin deficiency will first be determined. Also, whether leptin signaling or other signaling pathways are involved in this behavioral phenotype will be examined. Finally, as interferon is the major inducer of Ifitm genes expression, whether interferons act as negative regulator of feeding behavior will also be tested. Combining these results, profound background information about this phenomenon will be collected for further insight investigation, which might lead to identifying a novel controlling pathway of feeding behavior and energy homeostasis. The outcome of this research project will extend our understandings of hyperphagia and potentially might develop novel therapeutic strategy for treating this health issue. |
| Relation: | 科技部, MOST104-2320-B004-001, 104.08-105.07 |
| Data Type: | report |
| Appears in Collections: | [神經科學研究所] 國科會研究計畫
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