BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

有几条证据支持这样一种假设，即进食和身体 肥胖症是由循环因子调节的，这些因子反映了 脂肪商店。其中一个候选是胰腺激素胰岛素，它 可能通过几种途径调节中枢神经系统中的肥胖和体重 机制，包括食物摄入量、产热和代谢率(1- 5)。胰岛素可能通过受体介导的跨细胞转运进入中枢神经系统 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。拟议的研究重点放在 我观察到胰岛素增强内源性的机制(S) 中枢神经系统内去甲肾上腺素能活动(7)。中枢神经系统去甲肾上腺素能通路的作用 在摄食调节(8)和产热调节(9)中起关键作用。我 现在有证据表明这一行动背后的特定机制 胰岛素：胰岛素下调功能、数量和稳定状态的信使核糖核酸 去甲肾上腺素再摄取转运体(NET)的水平。抑制 重新摄取应该引起突触去甲肾上腺素(NE)的增加 浓度。这项更新提案中的研究解决了假设 胰岛素是中枢神经系统去甲肾上腺素能活动的生理调节因子 通过它对NE转运体的调节，以及b)胰岛素的这一作用 可能有助于其中枢神经系统作为能量平衡的调节器和 体重。胰岛素对中枢去甲肾上腺素能神经系统的调节作用 遗传性(Zucker fa/fa大鼠)和 饮食肥胖。这可能导致行为效能受损。 这些模型中的胰岛素含量。NE转运体的膜浓度将是 通过~3H-地昔帕明与脑膜的胰岛素-或 车辆处理过的大鼠。NE转运蛋白mRNA将通过原位检测进行评估 杂交。胰岛素后测定中枢神经系统对~3H-NE的摄取 体外或体内治疗。胰岛素对突触后的影响 将通过测量中枢肾上腺素能来评估对去甲肾上腺素神经元的影响 体内胰岛素后受体及主要受体偶联细胞信号 治疗。体重正常的Wistar大鼠，饮食肥胖的Wistar大鼠，以及 遗传肥胖的扎克大鼠将作为模型。把这些研究放在一起 应该可以让我确定胰岛素的体外和体内容量 调节去甲肾上腺素神经元的突触功能，并评价其变化 它们的基础和胰岛素调节功能与糖尿病的病理生理学 肥胖及其相关的中枢神经系统胰岛素抵抗。

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.