Leptin function & resistance in midbrain VTA & SN in reward eating & obesity

瘦素功能

• 批准号: 8391555
• 负责人: Yi none Zhang
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391555
• 关键词: Acute; Address; Affect; Animal Model; Area; Attenuated; Body Weight; Brain; Cannulas; Chronic; Chronic Disease; Consumption; Data; Diet; Disease; Dose; Eating; Energy Metabolism; Epidemic; Event; Exposure to; Fatty acid glycerol esters; Figs - dietary; Food; Gene Delivery; General Population; Grant; Health; Health Care Costs; Homeostasis; Hour; Human; Hyperlipidemia; Hypertension; Hypothalamic structure; Implant; Intake; JAK2 gene; Lead; Leptin; Leptin resistance; Link; Mediating; Midbrain structure; Military Personnel; Mission; Motor Activity; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Patient Care; Physiological; Population; Prevalence; Prosencephalon; Public Health; Rattus; Recombinant adeno-associated virus (rAAV); Regulation; Rehabilitation therapy; Resistance; Rewards; Rodent; Role; STAT3 gene; Signal Transduction; Simulate; Site; Societies; Sprague-Dawley Rats; Structure of nucleus infundibularis hypothalami; Substantia nigra structure; Testing; United States; Ursidae Family; Ventral Tegmental Area; Veterans; Weight Gain; Work; attenuation; care systems; design; disability; energy balance; feeding; food consumption; insight; interest; leptin receptor; male; mind control; nigrostriatal dopaminergic pathway; obesity treatment; overexpression; preference; public health relevance; receptor; receptor function; research study; response; reward circuitry

DESCRIPTION (provided by applicant): Obesity is prevalent in the United States. Diet-induced obesity (DIO) is the most common type of obesity and a major health-threatening chronic disease. Over-consumption of energy-dense, palatable food beyond basic caloric need promotes DIO. Recent data underpin a direct leptin function in the ventral tegmental area (VTA) of the midbrain reward circuitry to temper high-fat (HF) feeding. Our latest preliminary studies demonstrate (1) leptin activation of the VTA has a greater counter-regulatory function against HF intake and associated weight gain than that of the forebrain arcuate nucleus (ARC) of the hypothalamus; (2) a new physiological function of leptin to curtail weight gain in the substantia nigra (SN), another area within the midbrain reward circuitry. This proposal will investigate the role of leptin and leptin resistance specifically in the VTA and/or SN in modulating HF consumption and dietary weight gain and also address if these functions are especially important besides those in the hypothalamic ARC. We hypothesize that leptin function in the midbrain VTA, in particular, counters HF intake and contributes jointly with that in the forebrain ARC to the overall control of energy balance. We further postulate that HF feeding induces leptin resistance characterized by diminished food and body weight responses to leptin within the VTA, and that this resistance is a major culprit for exacerbating dietary obesity. Lastly, we propose a new role of leptin in energy homeostasis in the SN, and hypothesize that leptin directly regulates feeding and body weight in the SN and that leptin action in the SN contributes separately from that of the VTA to curb dietary weight gain. Three Specific Aims will be carried out in male Sprague Dawley (SD) rats. Aim 1 will address if leptin action in the VTA and in the ARC works in concert to curtail HF consumption and deter dietary weight gain. Aim 1 will also evaluate leptin function in the VTA to decrease the preference for HF food using a diet-selection paradigm compared to leptin effect in the ARC. Leptin will be chronically over-expressed via site-directed, recombinant adeno-associated virus-mediated (rAAV) gene delivery specifically to either the VTA, or ARC or both sites. Aim 2 seeks to identify a presumed leptin resistance in the VTA with chronic HF exposure and to establish a causal role of leptin resistance in the VTA to promote greater DIO. The onset of leptin resistance with chronic HF exposure in the VTA will be examined by assessing acute maximal leptin signaling in brain micro-punches and central leptin responsiveness. The latter will be determined from 24-hour food intake and body weight responses to a single dose of leptin introduced via implanted brain cannula in the VTA or ARC. Moreover, leptin resistance will be simulated by leptin receptor blockade achieved via rAAV-mediated leptin antagonist over-expression specifically in either the VTA or ARC, and the effect of this blockade in either site on HF consumption and dietary weight gain compared. Aim 3 is designed to validate the newly proposed leptin physiological function in the SN on energy homeostasis and/or reward eating. Potential effects of leptin in the SN will be compared to those in the VTA. Leptin will be over-expressed in the SN or VTA, or in both sites simultaneously via rAAV-leptin gene delivery in chow-raised rats remaining on chow or introduced to a HF diet. Food consumption, body weight gain, and energy expenditure including locomotor activity will be examined along with JAK2-STAT3 and/or ERK leptin signaling. It is of particular interest to explore if leptin over- expression in both the VTA and SN, simultaneously, will display an additive or synergistic inhibition of HF food intake and associated obesity compared to overexpression in either site alone. The outcomes of this application will provide valuable insights into new brain mechanisms governing reward eating and diet-induced obesity. The new information may lead to better strategies to address the looming obesity epidemic.

描述（由申请人提供）： 肥胖在美国很普遍。饮食诱导的肥胖症（Diet-induced obesity，DIO）是最常见的肥胖类型，也是一种严重威胁健康的慢性疾病。过度消耗能量密集，美味的食物超过基本的热量需求促进DIO。最近的数据支持中脑奖励回路腹侧被盖区（VTA）的直接瘦素功能，以调节高脂肪（HF）喂养。我们最新的初步研究表明：（1）腹侧被盖区的瘦素激活比下丘脑的前脑弓状核（ARC）对HF摄入和相关体重增加具有更大的反调节功能;（2）瘦素在黑质（SN）中减少体重增加的新生理功能，黑质是中脑奖励回路中的另一个区域。该提案将研究瘦素和瘦素抵抗在调节HF消耗和饮食体重增加中的作用，特别是在VTA和/或SN中，并且还将解决这些功能是否除了下丘脑ARC中的功能之外特别重要。我们假设瘦素在中脑腹侧被盖区的功能，特别是，计数器HF的摄入量，并有助于与前脑ARC的整体控制能量平衡。我们进一步假设，HF喂养诱导瘦素抵抗，其特征在于减少食物和体重反应瘦素内腹侧被盖区，这种阻力是一个主要的罪魁祸首，加剧饮食性肥胖。最后，我们提出了一个新的作用，瘦素在能量平衡的SN，并假设瘦素直接调节喂养和体重的SN和瘦素的行动有助于单独从腹侧被盖区，以遏制饮食中的体重增加。将在雄性Sprague道利（SD）大鼠中进行三项特定目的。目的1将解决腹侧被盖区和腹侧被盖区中的瘦素作用是否协同作用以减少HF消耗并阻止饮食体重增加。目的1还将评价腹侧被盖区中的瘦素功能，以使用饮食选择范例与ARC中的瘦素效应相比降低对HF食物的偏好。瘦素将通过位点定向的重组腺相关病毒介导的（rAAV）基因特异性递送至VTA或ARC或这两个位点而长期过表达。目的2旨在确定慢性HF暴露的腹侧被盖区中的假定瘦素抵抗，并确定腹侧被盖区中瘦素抵抗的因果作用，以促进更大的DIO。将通过评估脑微穿孔中的急性最大瘦素信号传导和中枢瘦素反应性来检查VTA中慢性HF暴露的瘦素抵抗的发作。后者将根据24小时食物摄入和体重对通过VTA或ARC中植入的脑插管引入的单剂量瘦素的反应来确定。此外，瘦素抗性将通过经由rAAV介导的瘦素拮抗剂在VTA或ARC中特异性过表达实现的瘦素受体阻断来模拟，并且比较在任一位点中这种阻断对HF消耗和饮食体重增加的影响。目的3旨在验证新提出的瘦素在SN中对能量稳态和/或奖励进食的生理功能。将比较瘦素在SN中的潜在作用与在VTA中的潜在作用。瘦素将在SN或VTA中过表达，或在两个位点中同时通过rAAV-瘦素基因递送在保持食物或引入HF饮食的食物饲养大鼠中过表达。将沿着JAK 2-STAT 3和/或ERK瘦素信号传导检查食物消耗、体重增加和能量消耗（包括运动活动）。特别令人感兴趣的是探索与在任一位点单独过表达相比，在VTA和SN两者中同时过表达的瘦素是否将显示HF食物摄入和相关肥胖的加和或协同抑制。这一应用的结果将为控制奖励性进食和饮食诱导的肥胖的新大脑机制提供有价值的见解。新的信息可能会导致更好的策略来解决迫在眉睫的肥胖流行病。