HYPOTHALAMIC PEPTIDES, FOOD INTAKE, AND DIABETES

下丘脑肽、食物摄入和糖尿病

• 批准号: 6529459
• 负责人: Michael W Schwartz
• 金额: $ 30.96万
• 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/6529459
• 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为了解不受控制的胰岛素缺乏糖尿病如何影响进食行为提供了一个明确且可测试的模型。 该模型基于这样的假设：身体肥胖的负反馈控制涉及激素、胰岛素和瘦素，它们的循环浓度与身体脂肪含量成正比。 假设这些激素通过作用于离散的下丘脑信号系统（此处称为“中枢效应器途径”）来减少食物摄入和体重。 因此，不受控制的糖尿病引起的体重减轻会降低胰岛素和瘦素的循环水平，从而导致糖尿病性食欲亢进。 据推测，这种反应部分是通过激活下丘脑神经元引起的，这些神经元共同表达神经肽 Y (NPY) 和内源性黑皮质素受体拮抗剂，称为“Agouti 相关蛋白”(Agrp)（两者都会刺激食物摄入），并且通过抑制含有黑皮质素的神经元（减少食物摄入）。 本申请的目的是 1) 确定瘦素缺乏作为不受控制的糖尿病对这些下丘脑神经元影响的中介因素的重要性。 这将通过以精确替代瘦素缺乏的糖尿病小鼠的生理瘦素水平的剂量全身输注瘦素，并通过原位杂交测量这些神经肽mRNA的下丘脑表达来实现； 2）使用具有遗传性NPY缺陷的小鼠来检验NPY是糖尿病的食欲亢进反应所必需的假设； 3) 确定糖皮质激素是否与胰岛素、瘦素联合作用调节糖尿病大鼠下丘脑神经肽基因表达； 4) 确定不受控制的糖尿病是否会激活与控制食物摄入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食欲素的通路，以及糖皮质激素、瘦素或胰岛素水平的变化是否介导这些反应。这些研究将 1) 提高我们对糖尿病患者常见的行为障碍的理解，2) 有助于阐明参与能量稳态的激素与其作用靶标之间的相互作用。