BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

体重调节的行为生理学

• 批准号: 2444021
• 负责人: DIANNE FIGLEWICZ LATTEMANN
• 金额: $ 19.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444021
• 关键词: adipose tissue; bioenergetics; body weight; genetic strain; hormone regulation /control mechanism; in situ hybridization; insulin; insulin sensitivity /resistance; laboratory rat; membrane transport proteins; neuroendocrine system; neurotransmitter transport; norepinephrine; nutrient intake activity; nutrition related tag; obesity; receptor coupling; synapses; weight control

Several lines of evidence support the hypothesis that feeding and body adiposity are regulated by circulating factors which reflect the size of adipose stores. One such candidate is the pancreatic hormone insulin which may regulate body adiposity and body weight in the CNS via several mechanisms, including food intake, thermogenesis, and metabolic rate (1- 5). Insulin may enter the CNS via receptor-mediated transcytosis across brain capillary endothelial cells (6), and interact there with several different CNS neurotransmitter systems. Proposed studies focus upon the mechanism(s) underlying my observation that insulin enhances endogenous noradrenergic activity within the CNS (7). CNS noradrenergic pathways play a critical role in the regulation of feeding (8) and thermogenesis (9). I now have evidence for a specific mechanism underlying this action of insulin: insulin downregulates the function, number, and steady state mRNA levels of the norepinephrine re-uptake transporter (NET). Inhibition of re-uptake should cause increased synaptic norepinephrine (NE) concentrations. Studies in this renewal proposal address the hypotheses that a) Insulin is a physiological regulator of CNS noradrenergic activity via its regulation of the NE transporter, and b) This action of insulin may contribute to its CNS function as a regulator of energy balance and body weight. The efficacy of insulin to regulate CNS noradrenergic activity may be impaired in models of genetic (Zucker fa/fa rats) and dietary obesity. This may contribute to the impaired behavioral efficacy of insulin in these models. NE transporter membrane concentrations will be assessed by 3H-desipramine binding to brain membranes from insulin- or vehicle-treated rats. NE transporter mRNA will be assessed by in situ hybridization. CNS uptake of 3H-NE will be measured after insulin treatment in vitro or in vivo. Postsynaptic consequences of insulin effects on NE neurons will be assessed by measuring CNS adrenergic receptors and major receptor-coupled cell signals after in vivo insulin treatment. Normal weight Wistar rats, dietary-obese Wistar rats, and genetically obese Zucker rats will serve as models. Together these studies should allow me to determine the in vitro and in vivo capacity of insulin to regulate the synaptic function of NE neurons, and to evaluate changes of their basal and insulin-regulated function with the pathophysiology of obesity and its associated CNS insulin resistance.

几条证据支持这一假设，即进食和身体 肥胖症是由循环因子调节的， 脂肪储存。其中一个候选者是胰腺激素胰岛素， 可以通过几种途径调节CNS中的身体肥胖和体重 机制，包括食物摄入，产热，代谢率（1- （五）。胰岛素可通过受体介导的胞吞作用进入CNS， 脑毛细血管内皮细胞（6），并在那里与几个 不同的中枢神经递质系统。拟议的研究重点是 我观察到的胰岛素增强内源性 CNS内的去甲肾上腺素能活性（7）。中枢神经系统去甲肾上腺素能通路 在摄食（8）和产热（9）的调节中起关键作用。我 现在有证据表明这种作用的具体机制， 胰岛素：胰岛素下调功能、数量和稳态mRNA 去甲肾上腺素再摄取转运蛋白（NET）。抑制 再摄取应引起突触去甲肾上腺素（NE）增加 浓度的本更新提案中的研究涉及以下假设： a）胰岛素是CNS去甲肾上腺素能活性的生理调节剂 通过其对NE转运蛋白的调节，和B）胰岛素的这种作用 可能有助于其作为能量平衡调节器的CNS功能， 体重胰岛素对中枢神经系统去甲肾上腺素能的调节作用 活性可能在遗传模型（Zucker fa/fa大鼠）中受损， 饮食性肥胖这可能会导致行为效能受损 胰岛素的浓度。NE转运蛋白膜浓度将 通过3 H-地昔帕明与胰岛素或 载体处理的大鼠。NE转运蛋白mRNA将通过原位杂交进行评估。 杂交方法将在胰岛素给药后测量3 H-NE的CNS摄取 体外或体内治疗。胰岛素的突触后效应 对NE神经元的影响将通过测量CNS肾上腺素能 受体和主要受体偶联细胞信号后，在体内胰岛素 治疗 正常体重Wistar大鼠、饮食肥胖Wistar大鼠和 遗传肥胖的Zucker大鼠将作为模型。这些研究 可以让我确定胰岛素在体外和体内的能力 调节NE神经元的突触功能，并评估变化 他们的基础和胰岛素调节功能与病理生理学 肥胖及其相关的CNS胰岛素抵抗。