HYPOTHALAMIC PEPTIDES, FOOD INTAKE, AND DIABETES

下丘脑肽、食物摄入和糖尿病

• 批准号: 6393639
• 负责人: Michael W Schwartz
• 金额: $ 30.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393639
• 关键词: adipose tissue; appetite regulatory center; behavioral /social science research tag; bioenergetics; gene expression; genetically modified animals; glucocorticoids; homeostasis; hormone regulation /control mechanism; hypothalamus; in situ hybridization; insulin; insulin dependent diabetes mellitus; laboratory mouse; laboratory rat; leptin; neuroendocrine system; neuropeptide Y; neuropeptides; nutrient intake activity; nutrition related tag; pathologic process; proopiomelanocortin; streptozotocin

Recent advances in the physiology of energy homeostasis provide a well-defined and testable model for understanding how uncontrolled insulin-deficient diabetes mellitus affects feeding behavior. This model is based on the hypothesis that negative feedback control of body adiposity involves the hormones, insulin and leptin, that circulate at concentrations proportional to body fat content. These hormones are hypothesized to reduce food intake and body weight by acting upon discrete hypothalamic signaling systems, referred to here as "central effector pathways." The effect of weight loss induced by uncontrolled diabetes to lower circulating levels of insulin and leptin is thus proposed to cause diabetic hyperphagia. This response is hypothesized to result in part via activation of hypothalamic neurons that co-express neuropeptide Y (NPY) and an endogenous melanocortin receptor antagonist, known as "Agouti-related protein" (Agrp) (both of which stimulate food intake), and by the inhibition of neurons that contain melanocortins (which reduce food intake). The objectives of this application are 1) to determine the importance of leptin deficiency as a mediator of the effect of uncontrolled diabetes on these hypothalamic neurons. This will be accomplished by infusing leptin systemically at a dose that precisely replaces the physiological leptin level in diabetic mice that are leptin-deficient, and by measuring hypothalamic expression of these neuropeptide mRNAs by in situ hybridization; 2) To use mice with genetic NPY deficiency to test the hypothesis that NPY is required for the hyperphagic response to diabetes; 3) To determine whether glucocorticoid hormones act in combination with insulin and leptin to regulate hypothalamic neuropeptide gene expression in diabetic rats; and 4) to determine if uncontrolled diabetes activates other hypothalamic neuropeptide systems implicated in the control of food intake, such as pathways containing melanin concentrating hormone and the orexins, and whether changing levels of glucocorticoids, leptin or insulin mediate these responses. These studies will 1) improve our understanding of a behavioral disorder commonly encountered among patients with diabetes, and 2) help to clarify the interactions between hormones involved in energy homeostasis and the targets upon which they act.

能量稳态生理学的最新进展提供了一个明确且可测试的模型，以了解不受控制的缺陷胰岛素缺乏糖尿病如何影响喂养行为。 该模型基于以下假设：对身体肥胖的负反馈控制涉及激素，胰岛素和瘦素，它们以与体内脂肪含量成正比的浓度循环。 假设这些激素是通过对离散的下丘脑信号系统作用，以减少食物摄入和体重，此处称为“中央效应途径”。 因此，提出了不受控制的糖尿病对较低循环水平的胰岛素和瘦素水平诱导的体重减轻的影响，以引起糖尿病性心phagia。 假设这种反应是通过激活下丘脑神经元的一部分，即神经肽Y（NPY）和内源性黑色皮质素受体拮抗剂，称为“与Agouti相关的蛋白质”（AGRP）（两者都刺激食物的蛋白质），以及抑制神经元的食物（减少食物（减少食物））（这两者都减少了食物（这两者）。 该应用程序的目标是1）确定瘦素缺乏症作为不受控制的糖尿病对这些下丘脑神经元影响的介体的重要性。 这将通过以剂量的剂量进行瘦素来实现，该剂量精确地替代了缺乏瘦素的糖尿病小鼠的生理瘦素水平，并通过原位杂交测量这些神经肽mRNA的下丘脑表达。 2）使用具有遗传NPY缺乏症的小鼠来检验以下假设：糖尿病对糖尿病的质量反应是必需的； 3）确定糖皮质激素是否与胰岛素和瘦素结合起作用，以调节糖尿病大鼠中下丘脑神经肽基因的表达； 4）为了确定不受控制的糖尿病是否激活了与食物摄入控制有关的其他下丘脑神经肽系统，例如含有黑色素浓缩激素和Orexins的途径，以及糖皮质激素，瘦素或胰岛素介导这些反应的变化。这些研究将1）提高我们对糖尿病患者通常遇到的行为障碍的理解，以及2）有助于阐明与能量稳态有关的激素与其作用的靶标之间的相互作用。