Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2403405. doi: 10.1002/advs.202403405. Epub 2024 Sep 11.
Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural-specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high-fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity-induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD-induced obesity and associated depression. Thus, a WFS1-ZnT3-Zn axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.
肥胖是一个日益严重的全球健康问题，与抑郁症密切相关。然而，肥胖和抑郁症之间关联的神经机制仍知之甚少。在这项研究中，神经特异性 WFS1 缺乏会加剧高脂肪饮食喂养的小鼠中肥胖和抑郁症的恶性循环，将 WFS1 定位为该循环中的关键因素。通过人类多能干细胞（hESC）的神经分化，证明 WFS1 通过抑制脂质代谢失调时的锌转运蛋白 ZnT3 来调节 Zn 稳态和神经祖细胞（NPC）和脑类器官的凋亡。值得注意的是，利鲁唑通过调节 ZnT3 表达来维持锌稳态并防止 NPC 受到脂毒性诱导的细胞死亡。重要的是，作为一种针对神经系统的治疗性分子，利鲁唑的体内给药可预防 HFD 诱导的肥胖和相关的抑郁症。因此，证明了肥胖和抑郁症恶性循环的关键是 WFS1-ZnT3-Zn 轴，并且利鲁唑可能具有逆转肥胖和抑郁症这一过程的潜力。
