Decreased CNS leptin activity in co-morbid depression and obesity

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%的美国成年人口可能被归类为超重或肥胖[1]。退伍军人中肥胖的发生率甚至更高，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，肥胖的并发症会延伸到中枢神经系统(CNS)。肥胖的神经系统并发症之一是增加了患抑郁症等共病的风险。在肥胖表型中，血浆瘦素升高，但血脑屏障(BBB)的瘦素转运受损，提示脑内瘦素抵抗可能是肥胖与重大抑郁性疾病之间的机制联系。这种瘦素抵抗可能与瘦素BBB转运减少和瘦素受体(Lepr)信号减少有关。这一建议的主要假设是，大脑瘦素抵抗代表了肥胖症合并抑郁的病因和进展中的一个机械性联系。这一假设将在两个创新的肥胖实验模型中得到验证：一种是选择性阻断瘦素血脑屏障运输的新型拮抗剂，另一种是使用选择性下调下丘脑胰岛素受体表达的慢病毒载体。在目标1中，我们将检测一种瘦素受体拮抗剂(LRA)的能力，它可以损害血脑屏障瘦素的运输，并造成中枢神经系统瘦素缺乏状态，从而引发抑郁和焦虑样行为。我们会 还要检查这些行为变化是否可逆。使用我们的低IRAs肥胖模型，我们将评估大脑瘦素水平和Lepr信号的减少是否与低IRAs大鼠抑郁样行为的发展有关(目标2)。在目标3中，我们将验证这样的假设，即食物限制恢复了瘦素和Lepr介导的信号的血脑屏障运输，从而逆转了在低IRAs大鼠中观察到的抑郁样表型。在目标4中，我们将检验一种已在VA患者中广泛研究的药物，即吉非罗齐，逆转肥胖啮齿动物的行为绝望和快感缺失的能力。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导致抑郁样行为的发展，这将增强我们对体重减轻和代谢参数正常化对肥胖者情绪和焦虑指标产生积极影响的机制的理解。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。这样的发现将直接适用于退伍军人管理局患者群体。

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.