肥胖為代謝疾病的一種症狀，已被證實與許多慢性疾病有很大的相關，成因主要由於體內過多能量盈餘並伴隨著代謝/儲存體內過多能量而產生的代謝性荷爾蒙，如胰島素與瘦素，經長期而引發代謝性荷爾蒙耐受性。其中瘦素已被證實與情感性疾病抑鬱症有關。臨床上抑鬱症病患的主要症狀有快感缺失等亦被發現與肥胖患者有較高相關性。而其中快感缺失的產生主要由中腦邊緣系統所釋放的多巴胺失調有關。數篇研究指出鉀離子通道在中腦邊緣系統中可以調控神經活性，進而影響多巴胺的釋放。其中三磷酸腺苷敏感型鉀離子通道，由胞內過少三磷酸腺苷開啟通道引起鉀離子流入細胞引發過極化，便能將代謝疾病與抑鬱症串聯再一起。我們假設三磷酸腺苷敏感型鉀離子通道在高脂飲食所引起抑鬱症扮演重要角色。我們發現八周大B6小鼠經12周高脂飼料餵食後在強迫游泳試驗和蔗糖偏愛試驗被發現有抑鬱樣行為。檢測腹側紋狀體神經傳導物進一步支持抑鬱症的表型。免疫墨點法、免疫呈色中發現肥胖小鼠的腹側紋狀體的三磷酸腺苷敏感型鉀離子通道。將三磷酸腺苷敏感型鉀離子通道阻斷劑以微滲透泵植入動物模式後發現血糖耐受性、抑鬱行為、血漿甘油三酯皆有改善。

Obesity, major feature in metabolic disorders (MetS), is associated with many chronic diseases and chronic positive energy balance causes the resistance of metabolic hormones including leptin which participate in the processing of medical depression. Clinically depressed patients have shown anhedonia, which also appeared in patients with obesity that indicate a dysregulation in mesolimbic DA system. Several studies indicate that potassium channels in mesolimbic system regulate the firing rate of DA neurons. Thus, adenosine triphosphate (ATP)-sensitive K+ (KATP) channels which are inward-rectifier potassium channel and act as a metabolic sensor to mediate electrical activity may link to metabolic disorder and depression. Hence, we hypothesize that neuronal KATP channels in the mesolimbic dopamine system play a key role in obesity-induced depression. We found 8 week old of B6 mice fed with 12 weeks of high-fat diet (HFD) showed depressive-like behaviors using forced swim test and sucrose preference test. The analysis of catecholamine showed the nucleus accumbens of HFD mice were further supported the depressive phenotype. Interestingly, total protein levels of KATP channel were elevated in the HFD mice using immunoblotting and immunostaining assays. Implantation of micro-osmotic pump containing either KATP channel blocker showed improved glucose tolerance, insulin tolerance, and depressive behavior as well as triglyceride levels.

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