Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin
Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin
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DOI：
10.1073/pnas.1415219111
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发表时间：
2014-11-04
影响因子：
11.1
通讯作者：
So, Kwok-Fai
中科院分区：
文献类型：
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作者：
Yau, Suk Yu;Li, Ang;So, Kwok-Fai
脂联素 (ADN) 是一种脂肪细胞分泌的蛋白质，具有胰岛素增敏、抗糖尿病、抗炎和抗动脉粥样硬化特性。越来越多的证据表明 ADN 具有神经保护活性，但其潜在机制仍然难以捉摸。在这里，我们证明 ADN 可以穿过血脑屏障，并且提高其在大脑中的水平会增加细胞增殖并减少抑郁样行为。 ADN 缺乏不会减少基底海马神经发生或神经元分化，但会降低运动增加海马神经发生的有效性。此外，运动引起的抑郁样行为减少在 ADN 缺陷小鼠中被消除，并且 ADN 缺陷小鼠中的这种损害伴随着跑步引起的海马组织中 AMP 激活蛋白激酶 (AMPK) 磷酸化的缺陷。体外分析表明，ADN 本身可以增加海马祖细胞和 Neuro2a 神经母细胞瘤细胞的增殖。 ADN 的神经源性作用是由 ADN 受体 1 (ADNR1) 介导的，因为靶向 ADNR1 而不是 ADNR2 的 siRNA 抑制了 ADN 增强细胞增殖的能力。这些数据表明，脂联素可能通过激活 ADNR1/AMPK 信号通路，在调节运动对海马神经发生和抑郁症的影响中发挥重要作用，并且还提出了脂联素及其激动剂可能代表抑郁症有前途的治疗方法的可能性。
Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.