Adiponectin signaling in mood regulation

脂联素信号在情绪调节中的作用

基本信息

批准号：
9249976
负责人：
Xin-Yun Lu
金额：
$ 3.71万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249976
关键词：
Ablation Adipose tissue Adult Affect Animal Model Antidepressive Agents Behavior Behavioral Behavioral Mechanisms Biological Brain Brain region Chronic Clinical Clinical Research Comorbidity Development Diabetes Mellitus Diabetic mouse Functional disorder Glycogen Synthase Kinase 3 Goals High Fat Diet 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 Stress Symptoms Testing Therapeutic Time Weight adipokines adiponectin adult neurogenesis base behavioral response clinically significant comorbid depression depressive behavior depressive symptoms diabetic in vivo insight kinase inhibitor knock-down mood regulation neurogenesis neuromechanism new therapeutic target non-diabetic novel novel therapeutics preclinical study public health relevance receptor severe mental illness social therapeutic target treatment strategy

项目摘要

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）：抑郁症是一种严重且常见的精神障碍，常与糖尿病等代谢性疾病共存。因此，识别和表征可能有益于抑郁症和糖尿病治疗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，被公认为是一种抗糖尿病脂肪因子。我们已经证明，脂联素不足会增加对抑郁样症状的易感性。相比之下，在正常体重小鼠和肥胖糖尿病小鼠中，向大脑施用外源脂联素会产生抗抑郁样作用，这表明脂联素在抑郁样行为中发挥着关键作用。该项目的目标是定义脂联素对抑郁行为作用的分子和细胞机制。脂联素受体 AdipoR1 和 AidpoR2 在海马体和内侧前额皮质 (mPFC) 中表现出不同的表达模式，这两个关键大脑区域与抑郁症和抗抑郁药的治疗作用有关。中枢注射脂联素可诱导神经元激活并刺激 p38MAPK（GSK-3b 抑制性磷酸化位点的上游激活剂）。此外，脂联素已被证明可以在体外刺激海马神经发生。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大脑区域、受体特异性的方式调节抑郁行为。我们建议确定 AdipoR1 和 AdipoR2 在抑郁样行为的发展和介导脂联素的抗抑郁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的作用的信号级联，并确定是否神经发生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开发。