第二型糖尿病是一種慢性代謝疾病，特徵包含胰島素阻抗以及胰臟受損。有研究指出患有第二型糖尿病的病人有更高的風險罹患憂鬱症。有研究指出臨床用的抗憂鬱藥Fluoxetine可有效降低病患體重。於此篇研究，我們想探討Fluoxetine 是否可以同時治療第二型糖尿病以及憂鬱症。於是我們藉著餵食高脂飼料12周(8周大)成功建立了同時患有代謝疾病以及憂鬱行為的老鼠。之後老鼠會每天被注射Fluoxetine持續4周，於四周治療期間發現老鼠的能量攝取比對照組少且體重持續減輕。四周治療結束後發現老鼠的葡萄糖耐受性以及胰島素阻抗被改善了，憂鬱行為也得到緩解。我們進一步發現受Fluoxetine治療的老鼠血中瘦素(leptin)降低了，這可能影響脂肪分解的活性，於是我們發現脂肪分解酵素ATGL與脂肪合成酵素PPARγ的活性下降。我們的研究指出ATGL的表現量下降會增加胰島素的敏感性，PPARγ的表現下降則會導致三酸甘油脂儲存在脂肪的量下降與先前的文獻一致。此外，有研究說明改善周邊胰島素阻抗就可以改善憂鬱行為，於是我們將餵食高脂飼料12周後的老鼠換回正常飲食，4周後發現這些老鼠體重以及代謝疾病包括胰島素阻抗被改善了，但是憂鬱行為卻沒有得到緩解。由此得知Fluoxetine可以有效地治療代謝疾病以及憂鬱症。

Type 2 diabetes is a chronic metabolic disorder characterized by insulin resistance and impaired pancreatic β-cell function. Many studies had demonstrated that patients with type 2 diabetes mellitus have more risk to develop depression. Fluoxetine, a selective serotonin reuptake inhibitor, is drug for mood and anxiety disorders. Previous studies showed that fluoxetine can induce weight loss in non-depressed clinically overweight individuals. In this study, we want to investigate whether fluoxetine could be a therapeutic drug against diabetes associated depression. We generated metabolic disorders and depressed mouse model by feeding high-fat diet (HFD) for 12 weeks from 8 weeks of age. Then, Mice were intraperitoneally injected once daily with fluoxetine for four weeks. Our results showed that obese mice treated with fluoxetine had a reduction in the body weight and calorie intake between treatment periods. Fluoxetine improved the ability of glucose-induced stimulation of insulin secretion and insulin sensitivity in metabolic disorder mice. Moreover, fluoxetine improved HFD-induced depression-like behaviors in mice. In metabolic disorder mice, fluoxetine reduced circulating plasma leptin level, and decreased the expression of ATGL and PPARγ in white adipose tissue. Our data revealed that fluoxetine also reduced the triglyceride synthesis in white adipose tissue.
Furthermore, previous studies suggested that depressive disorder could be improved by reversing insulin resistance. Thus, we designed another protocol to feed mice with normal chow instead of fluoxetine treatment after 12 week HFD. Our results showed that lower fat intake could improve glucose intolerance and insulin intolerance of these mice, in contrast, these mice still displayed depression-like behaviors. Therefore, fluoxetine is a better therapeutic efficacy to treat mice suffer from metabolic disorder and depression-like behaviors.

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