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: 8598798
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598798
• 关键词: Adipocytes; Adult; Anhedonia; Animals; Anxiety; Area; Behavior; Behavioral; Blood - brain barrier anatomy; Body Weight; Brain; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical Research; Comorbidity; Complication; Development; Down-Regulation; Epidemic; Epidemiologic Studies; Etiology; Exhibits; Experimental Models; Gemfibrozil; General Population; Goals; Healthcare; Hippocampus (Brain); Hormones; Hypothalamic structure; Impairment; Incidence; Individual; Insulin Receptor; Intervention; Investigation; Lentivirus Vector; Leptin; Leptin resistance; Life Style; Link; Measures; Mediator of activation protein; Mental Depression; Metabolic; Metabolic syndrome; Modeling; Moods; Morbid Obesity; Neuraxis; Neurologic; Obesity; Overweight; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prevalence Study; Rattus; Receptor Signaling; Recording of previous events; Risk; Rodent; Role; Site; Subfamily lentivirinae; Synaptic plasticity; Testing; Therapeutic Intervention; Triglycerides; United States Department of Veterans Affairs; Ventral Tegmental Area; Veterans; cost; depressive symptoms; epidemiology study; food restriction; health administration; innovation; leptin receptor; lifestyle intervention; novel; patient population; public health relevance; receptor expression; receptor-mediated signaling; research study; socioeconomics; success; translational approach; treatment strategy

DESCRIPTION (provided by applicant): Ongoing epidemiological studies by the Centers for Disease Control estimate that greater than 60% of the adult US population may be categorized as either overweight or obese [1]. The incidence of obesity is even greater in the VA population, with current estimates suggesting that over 72% of veterans may be classified as obese or overweight [2]. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). One of the neurological complications of obesity is an increased risk of developing co-morbidities like depressive illness. In obesity phenotypes, plasma leptin is increased but leptin transport across the blood-brain barrier (BBB) is impaired, suggesting that brain leptin resistance may be a mechanistic link between obesity and major depressive illness. This leptin resistance may be related to a combination of decreased leptin BBB transport and reduced leptin receptor (LepR) signaling. The overarching hypothesis of this proposal is that brain leptin resistance represents a mechanistic link in the etiology and progression of co-morbid depression in obesity. This hypothesis will be tested in two innovative experimental models of obesity: a novel antagonist that selectively blocks BBB transport of leptin and using a lentivirus vector that selectively downregulates hypothalamic insulin receptor expression (hypo-IRAS). In Aim 1 we will examine the ability of a leptin receptor antagonist (LRA) that impairs BBB leptin transport and creates a CNS leptin deficient state to elicit depressive-like and anxiety-like behaviors. We will also examine whether these behavioral changes are reversible. Using our hypo-IRAS model of obesity, we will assess whether decreases in brain leptin levels and LepR signaling are responsible for the development of depression-like behaviors in hypo-IRAS rats (Aim 2). In Aim 3, we will test the hypothesis that food restriction restores BBB transport of leptin and LepR-mediated signaling, thereby reversing the depressive-like phenotype observed in hypo-IRAS rats. In Aim 4, we will examine the ability of a drug that has been extensively studied in VA patients, namely gemfibrozil, to reverse behavioral despair and anhedonia in obese rodents. Successful completion of these studies will directly test our hypothesis that CNS leptin resistance elicits the development of depressive-like behaviors, which would enhance our understanding of the mechanisms through which reductions in body weight and normalization of metabolic parameters have positive effects on mood and anxiety measures in obese individuals. Most importantly, our studies will examine the ability of lifestyle and pharmacological interventions to reverse the depression-like phenotypes in obese rodents. Such findings would be directly translatable to VA patient populations.

描述（由申请人提供）： 疾病控制中心正在进行的流行病学研究估计，超过 60% 的美国成年人可能属于超重或肥胖 [1]。退伍军人群体中肥胖的发生率更高，目前的估计表明超过 72% 的退伍军人可能属于肥胖或超重 [2]。人们越来越认识到肥胖的并发症会影响中枢神经系统（CNS）。肥胖的神经系统并发症之一是患抑郁症等并发症的风险增加。在肥胖表型中，血浆瘦素增加，但瘦素跨血脑屏障（BBB）的转运受损，这表明大脑瘦素抵抗可能是肥胖和重度抑郁症之间的机制联系。这种瘦素抵抗可能与瘦素 BBB 转运减少和瘦素受体 (LepR) 信号传导减少有关。该提议的总体假设是，大脑瘦素抵抗代表了肥胖症共病抑郁症的病因和进展的机制联系。这一假设将在两个创新的肥胖实验模型中进行测试：一种新型拮抗剂，选择性阻断瘦素的 BBB 转运，并使用选择性下调下丘脑胰岛素受体表达 (hypo-IRAS) 的慢病毒载体。 在目标 1 中，我们将研究瘦素受体拮抗剂 (LRA) 损害 BBB 瘦素转运并造成中枢神经系统瘦素缺乏状态以引发抑郁样和焦虑样行为的能力。 我们将 还要检查这些行为变化是否是可逆的。使用我们的低 IRAS 肥胖模型，我们将评估脑瘦素水平和 LepR 信号传导的降低是否导致低 IRAS 大鼠出现抑郁样行为（目标 2）。在目标 3 中，我们将检验以下假设：食物限制可恢复瘦素的 BBB 转运和 LepR 介导的信号传导，从而逆转在低 IRAS 大鼠中观察到的抑郁样表型。在目标 4 中，我们将检查一种已在 VA 患者中进行广泛研究的药物（即吉非贝齐）逆转肥胖啮齿动物的行为绝望和快感缺乏的能力。 这些研究的成功完成将直接检验我们的假设，即中枢神经系统瘦素抵抗会引起抑郁样行为的发展，这将增强我们对体重减轻和代谢参数正常化对情绪和焦虑措施产生积极影响的机制的理解在肥胖者中。最重要的是，我们的研究将检验生活方式和药物干预逆转肥胖啮齿动物抑郁样表型的能力。这些发现将直接适用于 VA 患者群体。