Decreased CNS leptin activity in co-morbid depression and obesity

抑郁症和肥胖共病时中枢神经系统瘦素活性降低

• 批准号: 9898283
• 负责人: LAWRENCE P REAGAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898283
• 关键词: Address; Adult; Affect; Basic Science; Behavior; Behavioral; Biological Markers; Body Weight decreased; Brain; Brain region; Chronic; Clinical Research; Clinical Sciences; Diet; Effectiveness; Enzymes; Essential Amino Acids; Exhibits; Female; Fluoxetine; Goals; Health; High Fat Diet; Hippocampus (Brain); Impairment; Incidence; Individual; Inflammation; Inflammatory; Kinetics; Leptin; Leptin resistance; Literature; Measures; Mental Depression; Moods; Morbid Obesity; Neuraxis; Non obese; Obesity; Overweight; Pathogenesis; Periodicity; Plasma; Play; Population; Rattus; Risk; Rodent; Role; Scanning; Serotonin; Site; Testing; Triglycerides; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Veterans; Weight maintenance regimen; comorbid depression; comorbidity; cytokine; depressive symptoms; epidemiology study; healthy lifestyle; improved; in vivo; inhibitor/antagonist; insight; lifestyle intervention; male; mood regulation; neurochemistry; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; preclinical study; programs; raphe nuclei; response; reuptake; therapy resistant; treatment strategy; uptake

The overarching goal of this proposal is to demonstrate obesity-induced neuroinflammation in the raphe nucleus decreases serotonin synthesis which decreases hippocampal serotonin levels, thereby providing a neurochemical mechanism for co-morbid depressive illness in obesity. The incidence of obesity is greater in the VA population when compared with the general adult US population, with current estimates suggesting that over 80% of Veterans may be classified as obese or overweight. The complications of obesity extend to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Unfortunately, these epidemiological studies cannot determine the neurochemical mechanism for this comorbidity. Clinical studies provide some insight into this unanswered question in that obese individuals are more likely to exhibit treatment resistance to serotonin selective uptake inhibitors (SSRIs) when compared to non- obese individuals. Obesity is characterized by chronic mild inflammation and neuroinflammation has been proposed to be responsible for decreases in serotonergic activity in co-morbid obesity and depression. In spite of these advances, several critical questions remain to be addressed: 1) is neuroinflammation increased in the raphe nucleus in obesity?; 2) does raphe nucleus neuroinflammation decrease serotonin (5-HT) synthesis in the raphe nucleus and thereby decrease hippocampal 5-HT levels? and 3) can we identify treatment strategies to reverse these changes and/or readily accessible biomarkers that drive this comorbidity? Decreases in brain 5-HT levels are proposed to be a critical factor in the pathogenesis of depressive illness. Interestingly, our ongoing studies suggest that hippocampal 5-HT levels are significantly reduced in obese rats, thereby providing a potential neurochemical mechanism through which obesity increases the risk of neuropsychiatric disorders. As the raphe nucleus is the primary site of synthesis of 5-HT in the brain, neuroinflammation in the raphe nucleus may be a critical site for the neurochemical deficits that drive depressive illness in obesity. In view of these observations, the hypothesis of this proposal is that leptin resistance in the raphe nucleus decreases hippocampal 5-HT efflux, thereby providing a neurochemical mechanism for comorbid depressive illness in obesity. This hypothesis will be tested in the following Aims.  Aim 1 will determine whether neuroinflammation in the raphe nucleus decreases 5-HT synthesis and SSRI responses in the hippocampus of obese male and female rodents.  Aim 2 will determine whether lifestyle interventions that are consistent with the VA MOVE! weight management program can reverse obesity-induced neuroinflammation, 5-HT deficits and depressive- like behaviors in obese rats. Collectively, these studies will identify raphe nucleus neuroinflammation as the locus and neurochemical mechanism for comorbid depressive illness in obese individuals. Most importantly, our studies will provide further evidence for the importance of the MOVE! Program, particularly as it relates to the improvement of neuropsychiatric health of obese Veterans.

该提案的总体目标是证明肥胖引起的神经炎症 Raphe核会降低5-羟色胺合成，降低了海马5-羟色胺水平， 从而提供了一种神经化学机制，可用于肥胖症中合并抑郁症。 与一般成年人相比，VA人群的肥胖事件更大 美国人口，目前的估计表明，超过80％的退伍军人可能被归类为肥胖 或超重。肥胖的并发症扩展到中枢神经系统（CNS），包括 增加了发展神经精神疾病（如抑郁疾病）的风险。不幸的是，这些 流行病学研究无法确定这种合并症的神经化学机制。临床 研究提供了对这个未解决问题的见解，因为肥胖的人更有可能 与非 - 肥胖的人。肥胖症的特征是慢性轻度炎症和神经炎症的特征 我们被认为负责在合并肥胖和 沮丧。尽管有这些进步，但仍有几个关键问题要解决：1）是 肥胖症中raphe核的神经炎症增加？ 2）raphe核神经炎症 减少raphe核中的5-羟色胺（5-HT）合成，从而减少海马5-HT 水平？ 3）我们可以确定扭转这些变化和/或容易访问的治疗策略 驱动这种合并症的生物标志物？ 有人认为大脑5-HT水平的降低是对的关键因素 抑郁症。有趣的是，我们正在进行的研究表明，海马5-HT水平是 肥胖大鼠的大大减少，从而通过 肥胖会增加神经精神疾病的风险。由于raphe核us是主要位置 大脑中5-HT的合成，Raphe核中的神经炎症可能是关键的部位 神经化学定义了在观察中驱动抑郁疾病的。鉴于这些观察， 该提议的假设是raphe核中的瘦素耐药性下降了海马 5-ht外排，从而提供了一种神经化学机制，用于合并症 肥胖。该假设将在以下目的中进行检验。 AIM1将确定raphe核中神经炎症是否会降低5-HT合成和 肥胖男性和雌性啮齿动物海马中的SSRI反应。 AIM2将确定与VA移动一致的生活方式干预措施是否！重量 管理程序可以逆转肥胖引起的神经炎症，5-HT定义和抑郁 - 就像肥胖大鼠中的行为一样。 总的来说，这些研究将确定raphe核神经炎症为基因座和神经化学 肥胖个体合并抑郁疾病的机制。最重要的是，我们的学习将 提供进一步的证据证明这一举动的重要性！程序，特别是与 肥胖退伍军人的神经精神健康的改善。