Adiponectin signaling in mood regulation

描述（申请人提供）：抑郁症是一种严重的常见精神障碍，通常与糖尿病等代谢性疾病并存。因此，识别和表征对抑郁症和糖尿病的治疗有潜在益处的治疗靶点将具有重要的临床意义。脂联素是一种几乎完全由白色脂肪组织分泌的激素，是公认的抗糖尿病脂肪因子。我们已经证明脂联素不足会增加抑郁样症状的易感性。相比之下，外源性脂联素给药的大脑产生抗抑郁样作用，在正常体重的小鼠和肥胖的糖尿病小鼠，表明脂联素在抑郁样行为的关键作用。本研究的目的是明确脂联素对抑郁行为的分子和细胞机制。脂联素受体AdipoR 1和AidpoR 2在海马和内侧前额叶皮层（mPFC）中显示出不同的表达模式，这两个关键的大脑区域与抑郁症和抗抑郁药的治疗作用有关。中枢注射脂联素诱导神经元活化并刺激GSK-3b抑制性磷酸化位点的上游激活剂p38 MAPK。此外，脂联素已被证明在体外刺激海马神经发生。基于这些发现，我们推测脂联素通过不同的分子和细胞机制以脑区域、受体特异性的方式调节抑郁行为。我们建议确定AdipoR 1和AdipoR 2在抑郁样行为的发展中的区域特异性作用以及介导脂联素的抗抑郁样作用，确定介导脂联素对抑郁样行为作用的信号级联，并确定神经发生是否有助于脂联素的行为效应。这些研究将为脂肪因子调节情绪相关行为提供新的见解，并导致抑郁症新疗法的发展。

DESCRIPTION (provided by applicant): Depression is a severe and common mental disorder and often coexists with metabolic disorders such as diabetes. Therefore, the identification and characterization of therapeutic targets that are potentially beneficial for the treatment of both depression and diabetes would be of great clinical significance. Adiponectin, a hormone secreted almost exclusively by white adipose tissue, is well recognized as an anti-diabetic adipokine. We have demonstrated that adiponectin insufficiency increases susceptibility to depression-like symptoms. By contrast, administration of exogenous adiponectin to the brain produces antidepressant-like effects in normal weight mice and in obese diabetic mice, suggesting a critical role for adiponectin in depressive-like behaviors. The goal of this project i to define the molecular and cellular mechanisms of adiponectin actions on depressive behaviors. Adiponectin receptors, AdipoR1 and AidpoR2, display distinct expression patterns in the hippocampus and medial prefrontal cortex (mPFC), two key brain regions implicated in depression and the therapeutic actions of antidepressants. Central injection of adiponectin induces neuronal activation and stimulates p38MAPK, an upstream activator of the inhibitory phosphorylation site of GSK-3b. Moreover, adiponectin has been shown to stimulate hippocampal neurogenesis in vitro. Based upon these findings, we hypothesize that adiponectin regulates depressive behaviors in a brain-region, receptor-specific manner through distinct molecular and cellular mechanisms. We propose to determine the region-specific roles of AdipoR1 and AdipoR2 in the development of depressive-like behaviors and in mediating the antidepressant-like effect of adiponectin, identify the signaling cascade that mediates actions of adiponectin on depressive-like behaviors, and determine whether neurogenesis contributes to the behavioral effect of adiponectin. These studies will provide novel insights into adipokine regulation of mood-related behaviors and lead to the development of novel therapies for depression.