PDF(Pubmed)
Abstract：
Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.
摘要：
肥胖与中枢神经系统（CNS）的慢性炎症有关，神经炎症已被证明对情绪和认知有不利影响。生长激素促分泌素受体（GHSR），促食欲激素ghrelin的生物学相关受体，主要在大脑中表达。我们先前的研究表明，神经元GHSR缺失可预防高脂饮食诱导的肥胖（DIO）。这里,我们研究了神经元GHSR缺失对DIO情绪和认知功能的影响。与DIO下的同窝对照相比，神经元特异性GHSR缺陷型小鼠表现出降低的抑郁和改善的空间记忆。我们进一步检查了大脑皮层和海马,调节认知和情绪行为的主要区域，发现GHSR的神经元缺失通过抑制促炎趋化因子/细胞因子和减少小胶质细胞活化来减少DIO诱导的神经炎症。此外，我们的数据显示,神经元GHSR缺失通过下调神经元中的AMPK-自噬信号传导来抑制神经炎症.总之,我们的数据显示，神经元GHSR抑制保护免受DIO诱导的抑郁样行为和空间认知功能障碍，至少在某种程度上,通过AMPK-自噬信号介导的神经炎症。
