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; 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％的美国人群可能被归类为超重或肥胖[1]。在VA人群中，肥胖的发生率更大，目前的估计表明，超过72％的退伍军人可能被归类为肥胖或超重[2]。越来越多的欣赏肥胖症扩展到中枢神经系统（CNS）。肥胖的神经系统并发症之一是增加抑郁症（例如抑郁症）的风险。在肥胖表型中，血浆瘦素的增加增加，但瘦素遍布血脑屏障（BBB），这表明脑瘦素的耐药性可能是肥胖症与重度抑郁疾病之间的机械联系。该瘦素耐药性可能与瘦素BBB转运和瘦素受体（LEPR）信号降低的组合有关。该提议的总体假设是，脑瘦素的抗性代表了肥胖症中合并抑郁症的病因和进展中的机械联系。该假设将在肥胖的两个创新实验模型中进行检验：一种新型拮抗剂，有选择地阻断瘦素的BBB转运，并使用慢病毒载体有选择地下调下丘脑胰岛素受体表达（Hypo-IRAS）。 在AIM 1中，我们将检查瘦素受体拮抗剂（LRA）的能力，该瘦素受到BBB瘦素的运输，并创建CNS瘦素缺乏状态以引起抑郁症状和焦虑症状。 我们将 还要检查这些行为变化是否可逆。使用我们的肥胖模型，我们将评估脑瘦素水平降低和LEPR信号的降低是否导致降压性IRAS大鼠的抑郁样行为的发展（AIM 2）。在AIM 3中，我们将测试以下假设：食物限制恢复了瘦素和LEPR介导的信号传导的BBB转运，从而逆转了在Hypo-IRAS大鼠中观察到的抑郁样表型。在AIM 4中，我们将研究已在VA患者（即Gemfibrozil）中进行广泛研究的药物的能力，以逆转肥胖啮齿动物中的行为绝望和Anhedonia。 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耐药性会引起抑郁样行为的发展，这将增强我们对降低体重和代谢参数归一化的机制的理解，对肥胖个体的情绪和焦虑措施具有积极影响。最重要的是，我们的研究将研究生活方式和药理学干预措施扭转肥胖啮齿动物中抑郁型表型的能力。此类发现将直接转化为VA患者人群。