Major depression disorder is a severe mental illness often linked with metabolic disorders. Adiponectin is an adipocyte-secreted circulatory hormone with antidiabetic and glucose/lipid modulation capacities. Studies have demonstrated the pathophysiological roles of adiponectin involved in various neurological disorders, including depression. However, the underlying mechanisms are poorly understood. Here we showed that adiponectin deprivation enhanced antidepressive-like behaviors in the LPS-induced model of depression. APN KO mice displayed increased cytokines (both pro and anti-inflammatory), accompanied by an impaired expression of adiponectin receptors (mRNA/protein level) and decreasing IBA-1 level in the cortex and primary microglia of LPS treated APN KO mice. Further, LPS-treatment significantly reduced p-NFκB expression in the microglia of APN KO mice. However, the Bay11-7082 treatment recovered p-NFκB expression in the cortex of APN KO mice in the presence of LPS. Interestingly, the antidepressant potentials of APN KO mice were abolished by TrkB antagonist K252a, IKK inhibitor Bay11-7082, and AdipoRon suggesting crosstalk between TrkB/BDNF signaling and NFκB in depression. Furthermore, the effects of Bay11-7082 were abolished by a TrkB/BDNF activator (7,8-DHF), indicating a critical role of TrkB/BDNF signaling. Taken together, these findings showed that dysregulated neuroinflammatory status and BDNF signaling might underlie the antidepressive-like behaviors of APN KO mice. NFκB elicited BDNF changes may be accountable for the pathogenesis of LPS induced depression, where APN might present an alternative therapeutic target for depressive disorders.

重度抑郁症是一种严重的精神疾病，通常与代谢紊乱有关。脂联素是一种脂肪细胞分泌的循环激素，具有抗糖尿病和葡萄糖/脂质调节能力。研究已经证明了脂联素在各种神经系统疾病（包括抑郁症）中的病理生理作用。然而，人们对基本机制知之甚少。在这里，我们表明脂联素剥夺增强了 LPS 诱导的抑郁症模型中的抗抑郁样行为。APN KO 小鼠表现出增加的细胞因子（促炎和抗炎），伴随着脂联素受体（mRNA/蛋白质水平）的表达受损以及 LPS 处理的 APN KO 小鼠皮质和原代小胶质细胞中 IBA-1 水平降低。更远，LPS 处理显着降低了 APN KO 小鼠小胶质细胞中的 p-NFκB 表达。然而，Bay11-7082 治疗在 LPS 存在的情况下恢复了 APN KO 小鼠皮质中的 p-NFκB 表达。有趣的是，APN KO 小鼠的抗抑郁潜力被 TrkB 拮抗剂 K252a、IKK 抑制剂 Bay11-7082 和 AdipoRon 消除，这表明抑郁症中 TrkB/BDNF 信号和 NFκB 之间存在串扰。此外，Bay11-7082 的作用被 TrkB/BDNF 激活剂 (7,8-DHF) 消除，表明 TrkB/BDNF 信号传导的关键作用。综上所述，这些发现表明失调的神经炎症状态和 BDNF 信号可能是 APN KO 小鼠抗抑郁样行为的基础。NFκB 引起的 BDNF 变化可能是 LPS 诱发抑郁症的发病机制，