Hepatic Metabolic Control of Meal Size and Number

肝脏对膳食量和数量的代谢控制

• 批准号: 6731272
• 负责人: WOLFGANG LANGHANS
• 金额: $ 18.45万
• 依托单位: SWISS FEDERAL INST OF TECH (ETH ZURICH)
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731272
• 关键词: adenosine triphosphate; afferent nerve; appetite; behavioral /social science research tag; bioenergetics; biofeedback; biological signal transduction; brain stem; carbohydrate metabolism; denervation; estradiol; fos protein; gender difference; gene targeting; genetically modified animals; glycogen; hypothalamus; immunocytochemistry; laboratory rat; lipid metabolism; liver metabolism; neuroendocrine system; nutrient intake activity; nutrition related tag; satiations; sex cycle

DESCRIPTION (provided by applicant): Because it has proven difficult to establish clearly the role of energy metabolism in the control of normal feeding, this application proposes behavioral, physiological, and genetic studies of the mechanisms by which hepatic metabolism controls normal spontaneous feeding in rats. Our hypothesis is that hepatic metabolic consequences of food ingestion generate negative feedback signals that reach the brain via vagal afferent neurons and act in the brain to terminate ingestion and limit meal size (i.e., produce satiation). Furthermore, we hypothesize that the relevant metabolic events result from the biochemical integration of hepatocellular glucose and fatty acid utilization and that they are modulated by liver glycogen content. Seven specific aims are proposed to determine: (1) whether changes in hepatocellular ATP energy status are sufficient to affect spontaneous meal size or meal number; whether hepatocellular utilization of carbohydrate or medium-chain fatty acids is sufficient to reduce spontaneous meal size or meal number; (2) whether changes in hepatocellular utilization of carbohydrate or medium-chain fatty acids are sufficient to affect spontaneous meal size or meal number; (3) whether hepatic glycogen content modulates the hepatocellular metabolic control of spontaneous feeding; (4) the role of the vagus nerve in hepatocellular metabolic control of spontaneous feeding; (5) which areas of the brainstem and hypothalamus are activated by manipulations of hepatocellular metabolic controls of spontaneous feeding; (6) whether there are estradiol-sensitive sex differences in hepatocellular metabolic controls of spontaneous feeding; and (7) if there are phenotypic differences in the hepatocellular control of meal size in transgenic rats with inducible over-expressions (knock in) of key enzymes of the putative hepatocellular metabolic pathways affecting meal size. Because disordered eating is a central feature anorexia nervosa, bulimia nervosa, and obesity and because metabolic controls of food intake may be disturbed in syndromes such as NIDDM, the proposed studies should contribute new basic physiological knowledge that may facilitate advances in understanding and treating human health problems. Work on this project will be done as a consortium to capitalize on the unique expertise of the PI at Swiss Federal Institute for Technology, Zurich, Switzerland, and the co-PI, at Weill Medical College of Cornell University, White Plains, NY.

描述（由申请人提供）：由于已证明很难明确确定能量代谢在控制正常进食中的作用，因此本申请提出对肝脏代谢控制大鼠正常自发进食的机制进行行为、生理和遗传研究。我们的假设是，食物摄取的肝代谢结果产生负反馈信号，该负反馈信号通过迷走神经传入神经元到达大脑，并在大脑中起作用以终止摄取并限制膳食量（即，产生饱足感）。此外，我们推测，相关的代谢事件的结果从肝细胞葡萄糖和脂肪酸利用的生化整合，它们是由肝糖原含量调制。提出了七个具体目标来确定：（1）肝细胞ATP能量状态的变化是否足以影响自发的进餐量或进餐次数;肝细胞对碳水化合物或中链脂肪酸的利用是否足以减少自发的进餐量或进餐次数;（2）肝细胞对碳水化合物或中链脂肪酸利用的变化是否足以影响自发的进餐量或进餐次数;（3）肝糖原含量是否调节自发摄食的肝细胞代谢控制;（4）迷走神经在自发摄食的肝细胞代谢控制中的作用;（5）脑干和下丘脑的哪些区域被自发摄食的肝细胞代谢控制的操纵激活;（6）自发进食的肝细胞代谢控制是否存在雌激素敏感性性别差异;以及（7）在具有影响膳食量的假定肝细胞代谢途径的关键酶的诱导性过表达（敲入）的转基因大鼠中，肝细胞对膳食量的控制是否存在表型差异。由于饮食失调是神经性厌食症、神经性贪食症和肥胖症的一个中心特征，并且由于食物摄入的代谢控制可能在NIDDM等综合征中受到干扰，因此拟议的研究应提供新的基础生理学知识，这可能有助于理解和治疗人类健康问题。本项目的工作将作为一个联合体完成，以利用瑞士苏黎世瑞士联邦理工学院PI和纽约州白原康奈尔大学威尔医学院共同PI的独特专业知识。