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Hepatic Metabolic Control of Meal Size and Number

肝脏对膳食量和数量的代谢控制

基本信息

批准号：
7220670
负责人：
WOLFGANG LANGHANS
金额：
$ 17.49万
依托单位：
SWISS FEDERAL INST OF TECH (ETH ZURICH)
依托单位国家：
美国
项目类别：
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/7220670
关键词：
Adenine Affect Afferent Neurons Animals Anorexia Nervosa Antimetabolites Area Behavioral Behavioral Research Biochemical Body Weight Brain Brain Stem Bulimia Carbohydrates Carnitine Communication Denervation Desire for food Eating Eating Disorders Energy Metabolism Enzymes Estradiol Event FOS Protein FOS gene Facility Construction Funding Category Fatty Acids Feedback Female Food Genetic Glucose Health Hepatic Hepatocyte Human Hypothalamic structure Infusion procedures Ingestion Institutes Knock-in Mouse Knowledge Laboratories Laboratory Research Lipids Liver Liver Glycogen Measurement Medical Medium chain fatty acid Metabolic Metabolic Control Metabolic Pathway Metabolism Methods Mitochondria Modeling Non-Insulin-Dependent Diabetes Mellitus Numbers Obesity Ovarian Cycles Performance at work Phenotype Physiological Portal vein structure Principal Investigator Protein Isoforms Proto-Oncogene Proteins c-fos Range Rate Rattus Research Design Resources Role Satiation Science Sex Characteristics Signal Transduction Site Switzerland Syndrome Techniques Technology Testing Transferase Transgenic Organisms Universities Vagus nerve structure Vena caval structure Work college disorder control fatty acid oxidation feeding immunocytochemistry lipid metabolism programs relating to nervous system size trait

项目摘要

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）：由于很难明确确定能量代谢在控制正常摄食中的作用，本申请提出对大鼠肝脏代谢控制正常自发摄食的机制进行行为、生理和遗传学研究。我们的假设是，食物摄入的肝脏代谢后果会产生负反馈信号，这些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，终止摄入并限制食物的大小（即产生饱腹感）。此外，我们假设相关代谢事件是由肝细胞葡萄糖和脂肪酸利用的生化整合引起的，并受到肝糖原含量的调节。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餐量或餐数；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餐量或餐数；(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餐量或餐数；(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进食的肝细胞代谢控制所激活；(6)自发喂养的肝细胞代谢控制是否存在雌二醇敏感的性别差异；(7)转基因大鼠的肝细胞对摄食量的控制是否存在表型差异，诱导影响摄食量的肝细胞代谢途径的关键酶过表达（敲入）。由于饮食失调是神经性厌食症、神经性贪食症和肥胖症的核心特征，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。该项目的工作将作为一个联盟来完成，以利用瑞士苏黎世瑞士联邦理工学院的PI和纽约州怀特普莱恩斯康奈尔大学威尔医学院的联合PI的独特专业知识。