Adiponectin signaling in mood regulation

脂联素信号在情绪调节中的作用

• 批准号: 8494322
• 负责人: Xin-Yun Lu
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494322
• 关键词: Ablation; Adipose tissue; Adult; Affect; Animal Model; Antidepressive Agents; Behavior; Behavioral; Behavioral Mechanisms; Biological; Brain; Brain region; Chronic; Clinical; Clinical Research; Development; Diabetes Mellitus; Diabetic mouse; Diet; Fatty acid glycerol esters; Functional disorder; Goals; Hippocampus (Brain); Hormones; In Vitro; Individual; Injection of therapeutic agent; Lead; Medial; Mediating; Medical; Mental Depression; Mental disorders; Metabolic Diseases; Modeling; Molecular; Mood Disorders; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pattern; Phenotype; Phosphorylation Site; Phosphotransferases; Plasma; Play; Population; Predisposition; Prefrontal Cortex; Prevalence; Property; Protein Isoforms; Risk; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Staging; Stress; Symptoms; Testing; Therapeutic; Time; Weight; adiponectin; adult neurogenesis; base; clinically significant; depressive symptoms; diabetic; in vivo; insight; kinase inhibitor; mood regulation; neurogenesis; neuromechanism; new therapeutic target; non-diabetic; novel; preclinical study; public health relevance; receptor; response; severe mental illness; social; therapeutic target; treatment strategy

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.

描述(申请人提供)：抑郁症是一种严重而常见的精神障碍，常与糖尿病等代谢障碍并存。因此，确定和表征对抑郁症和糖尿病治疗都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，是一种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，将外源性脂联素注射到大脑中，在正常体重的小鼠和肥胖的糖尿病小鼠中产生抗抑郁药样作用，这表明脂联素在抑郁样行为中起着关键作用。本项目的目标是确定脂联素在抑郁行为中作用的分子和细胞机制。脂联素受体AdipoR1和AidpoR2在海马区和内侧前额叶皮质(MPFC)表现出不同的表达模式，这两个区域与抑郁症和抗抑郁药物的治疗作用有关。中枢注射脂联素可诱导神经元激活，并刺激GSK-3b抑制磷酸化位点的上游激活物p38MAPK。此外，脂联素已被证明在体外可以刺激海马神经发生。基于这些发现，我们假设脂联素通过不同的分子和细胞机制，以受体特异性的方式调节大脑区域的抑郁行为。我们建议确定AdipoR1和AdipoR2在抑郁样行为的发生和介导脂联素的抗抑郁药样作用中的区域特异性作用，确定介导脂联素对抑郁样行为作用的信号级联反应，并确定神经发生是否参与脂联素的行为效应。这些研究将为脂肪因子对情绪相关行为的调控提供新的见解，并导致抑郁症新疗法的开发。