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）： 美国疾病控制中心正在进行的流行病学研究估计，超过60%的美国成年人口可能被归类为超重或肥胖[1]。肥胖的发病率在VA人群中甚至更高，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]。越来越多的人认识到，肥胖症的并发症扩展到中枢神经系统（CNS）。肥胖的神经系统并发症之一是患抑郁症等共病的风险增加。在肥胖表型中，血浆瘦素增加，但血脑屏障（BBB）的瘦素转运受损，表明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）信号传导减少的组合有关。这个建议的首要假设是，大脑瘦素抵抗代表了肥胖共病抑郁症的病因学和进展的机制联系。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，选择性地阻断血脑屏障转运瘦素和使用慢病毒载体，选择性下调下丘脑胰岛素受体表达（hypo-IRAS）。 在目的1中，我们将检查瘦素受体拮抗剂（LRA）的能力，它损害BBB瘦素转运，并创建一个CNS瘦素缺乏状态，以引起抑郁样和焦虑样行为。 我们将 也要检查这些行为变化是否可逆。使用我们的hypo-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是hypo-IRAS大鼠中抑郁样行为发展的原因（目的2）。在目标3中，我们将检验以下假设：食物限制恢复瘦素和瘦素受体介导的信号传导的血脑屏障转运，从而逆转在低IRAS大鼠中观察到的抑郁样表型。在目标4中，我们将研究一种在VA患者中广泛研究的药物，即吉非罗齐，逆转肥胖啮齿动物行为绝望和快感缺乏的能力。 这些研究的成功完成将直接验证我们的假设，即CNS瘦素抵抗导致抑郁样行为的发展，这将增强我们对肥胖个体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。最重要的是，我们的研究将检查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。这些发现将直接转化为VA患者人群。