肥胖及憂鬱症的盛行率在全球各國逐年增加， 近年來流行病學研究指出肥胖與憂鬱 症兩者有著高度關聯， 先前研究發現肥胖病人的棕色脂肪活性較低暗示著肥胖會影 響棕色脂肪功能， 棕色脂肪為一重要調控代謝之器官且能透過交感神經及分泌內分 泌因子與大腦溝通，三磷酸腺苷敏感型鉀離子通道 (KATP) 的開關受細胞膜內三磷酸 腺苷及二磷酸腺苷的比值所調控，進而影響細胞的代謝及興奮性，重要的是，先前有 一研究發現脂肪細胞缺少Kir6.2會增加脂肪葡萄糖攝取，暗示著三磷酸腺苷敏感型鉀離 子通道在脂肪細胞的功能。故此研究我們的假設為: 在棕色脂肪上的三磷酸腺苷敏感 型鉀離子通道在憂鬱症中扮演重要角色， 其機制可能是透過內分泌因子的釋放或交 感神經系統來調控憂鬱症狀。 從我們的研究發現， 高脂飲食除了使小鼠產生肥胖及 代謝症狀外，更可誘發類憂鬱症。 在棕色脂肪移除後小鼠也會出現類憂鬱行為，顯示 棕色脂肪參與在憂鬱症的發病過程中。我們確認了三磷酸腺苷鉀離子通道表現在棕色 脂肪上，在棕色脂肪給予三磷酸腺苷敏感型鉀離子通道抑制劑-格列苯脲後不僅改善 代謝失調更減少憂鬱症狀，且增加了棕色脂肪上的三磷酸腺苷鉀離子通道表現量。接 著我們發現棕色脂肪上的三磷酸腺苷鉀離子通道表現量的增加伴隨著交感神經活性上 升。受活化的β3 腎上腺素受體(β3-adrenergicreceptors)及其下游蛋白激酶A(protein kinase A)可以更增加三磷酸腺苷敏感型鉀離子通道的表現。針對內分泌因子方面， 我們發現格列苯脲給予使棕色脂肪細胞中的纖維細胞生長因子21 (FGF21) 表現量上 升，給予FGF21同樣可以改善代謝失調及減少憂鬱症狀，此外我們發現給予FGF21或 格列苯脲都可以恢復在腹側被蓋區多巴胺神經元上的FGF21受體(FGFR1, KLB)因 高脂飼料餵食而出現的失衡，並且增加多巴胺神經元的活性。 總合來說，我們認為活 化棕色脂肪上的三磷酸腺苷敏感型鉀離子通道， 能改善由高脂飲食所導致的憂鬱行為 這是透過調控交感神經系統及內分泌因子的釋放。

The prevalence rate of obesity and depression is increasing around the world, and epidemiological studies have shown that the two conditions often exist as comorbidities. Previous studies have also revealed that brown adipose tissue (BAT) activity is decreased in obese patients, which implies that obesity might affect BAT function. Importantly, BAT is a critical metabolism-regulating organ that can communicate with the brain through sympathetic nerves and BATokines. In addition, ATP-sensitive potassium (KATP) channels are known to couple the metabolic state of a cell to membrane excitability, as the channels are gated by the intracellular concentration of ATP and ADP. One particularly interesting recent study revealed that loss of the KATP channel subunit Kir6.2 in adipocytes increases glucose uptake, suggesting a functional role for the channel in adipose tissue. We therefore hypothesized that KATP channels in BAT may play an important role in depression, acting through the sympathetic nerve circuitry or BATokine release. To test this hypothesis, we used mice fed a high-fat diet (HFD), which developed both depression-like symptoms and metabolic syndrome. Since depressive symptoms could also be observed after the removal of BAT in control mice, our findings suggested a role for BAT in mood disorders. Next, we confirmed that KATP channels are functionally expressed in BAT, and we showed that infusion of the KATP channel blocker glibenclamide (GB) into BAT of HFD mice not only improved metabolic disorders but also reduced depression-like symptoms. GB infusion also restored HFD-induced decreases in BAT KATP channel expression. We further found that upregulation of KATP channels was correlated with increased sympathetic nerve innervation, and activation of β3-adrenergic receptor (β3 AR)-mediated protein kinase A (PKA) signaling stimulated forward trafficking of KATP channels. Regarding BATokine release, we found that GB treatment increased FGF21 levels in brown adipocytes both in vitro and in vivo. Then, we demonstrated that FGF21 treatment reduced metabolic disorder symptoms and improved depression-like behaviors in HFD-fed mice. Either FGF21 or GB treatment could reverse the dysregulation of FGF21 receptors caused by HFD feeding, as well as the dysregulated expression of FGFR1 and a co-receptor β-klotho (KLB), in the ventral tegmental area. Finally, we found that FGF21 or GB treatment increased dopaminergic neuron activity. Together, these findings suggest that activation of KATP channels in BAT can reverse HFD-induced depression-like symptoms through sympathetic innervation and BATokine release.

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