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

瘦素功能

• 批准号: 8195593
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195593
• 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

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.

肥胖在美国很普遍。饮食诱导的肥胖（DIO）是最常见的肥胖类型， 严重威胁健康的慢性疾病。过度食用高能量、可口的食物， 热量需求促进DIO。最近的数据支持瘦素在腹侧被盖区（VTA）的直接功能， 中脑奖励回路来调节高脂肪（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对HF摄入和相关体重具有更大的反调节功能 （2）脑神经元的一种新的生理功能， 瘦素来减少黑质（SN）的体重增加，黑质是中脑奖励回路中的另一个区域。这 一项提案将研究瘦素和瘦素抵抗的作用，特别是在VTA和/或SN中， HF消耗和饮食体重增加，并解决这些功能是否特别重要， 那些在下丘脑弧中的。我们假设瘦素在中脑腹侧被盖区的功能，特别是， 对抗HF摄入，并与前脑ARC中的共同作用， 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： 腹侧被盖区对瘦素的食物和体重反应减弱，这种抵抗是一种 是加剧饮食性肥胖的罪魁祸首最后，我们提出了瘦素在能量中的新作用 内稳态的SN，并假设瘦素直接调节喂养和体重的SN 并且SN中的瘦素作用与VTA的作用分别有助于抑制饮食性体重增加。 将在雄性Sprague道利（SD）大鼠中进行三项特定目的。目标1将解决如果瘦素的行动， VTA和ARC协同工作以减少HF消耗并阻止饮食体重增加。目标1将 还评估腹侧被盖区的瘦素功能，以使用饮食选择范例降低对HF食物的偏好 与瘦素在ARC中的作用相比。瘦素将通过定点、重组的方法长期过表达， 腺相关病毒介导的（rAAV）基因递送特异性地递送至VTA或ARC或这两个位点。 目的2试图确定慢性HF暴露的腹侧被盖区中假定的瘦素抵抗，并建立一个与慢性HF暴露相关的瘦素抵抗模型。 VTA中瘦素抵抗的因果作用促进更大的DIO。瘦素抵抗的发生与慢性 将通过评估脑微穿孔中的急性最大瘦素信号传导来检查VTA中的HF暴露 和中枢瘦素反应。后者将从24小时食物摄入量和体重来确定 通过在VTA或ARC中植入脑插管引入单剂量瘦素的反应。此外，委员会认为， 通过rAAV介导的瘦素拮抗剂实现的瘦素受体阻断将模拟瘦素抗性 在VTA或ARC中特异性过表达，以及在任一部位阻断对HF的影响 消耗和饮食体重增加进行比较。目的3是为了验证新提出的瘦素 在SN中的生理功能对能量稳态和/或奖励进食的影响。瘦素在糖尿病中的潜在作用 SN将与VTA中的SN进行比较。瘦素将在SN或VTA或两个部位过度表达 同时通过rAAV-瘦素基因递送在保持进食或引入HF饮食的进食饲养的大鼠中进行。 将检查摄食量、体重增加和能量消耗（包括自发活动） 沿着JAK 2-STAT 3和/或ERK瘦素信号传导。这是特别感兴趣的探索，如果瘦素过度- 同时在VTA和SN中的表达将显示HF食物的加和或协同抑制， 摄入和相关的肥胖相比，在任何一个网站单独的过度表达。这个结果 应用将提供有价值的见解，新的大脑机制，管理奖励进食和饮食诱导 肥胖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。