METABOLIC CONTROL OF FEEDING BEHAVIOR

描述(申请人提供)：吸收后的燃料代谢是控制食物摄入量的一个重要因素。大脑和肝脏中对各种代谢参数敏感的传感器与这种控制有关。在肝脏，相当多的证据表明，能量代谢的变化会产生一个或多个刺激，这些刺激被转化为神经信号，将代谢信息传递到中枢神经系统，用于控制食物的摄入量。特别是，肝脏ATP含量的变化或肝脏能量状态的一些密切相关的变化会产生信号，在不同的条件下启动或终止摄食行为，如禁食-再喂食、I型糖尿病和代谢抑制剂的治疗。该实验室最近的研究显示，三种不同的肥胖动物模型(遗传、饮食和神经)显示肝脏能量状态降低，这表明肝脏能量状态的变化也参与了暴饮暴食和肥胖的发展。该项目的总体目标是评估肝脏能量代谢改变是否以及如何导致导致肥胖的过度吞噬(暴饮暴食)。当喂食高脂肪含量的食物时，一些大鼠会暴饮暴食而变得肥胖(容易肥胖)，而另一些相同品系的大鼠则不会(抵抗肥胖)。这项拟议的研究将使用这种饮食诱导的肥胖动物模型，因为它似乎与人类常见的肥胖最相似。我们假设，在肥胖的发展过程中，吞噬功能亢进可能至少部分是由肝脏能量状态下降引起的，这是燃料重新定向到储存中而远离氧化途径的次要因素。暴饮暴食可能是由于两餐之间肝脏能量状态下降较快，或餐中和餐后肝脏能量状态恢复较慢所致。该项目有三个具体目标：(1)确定肥胖倾向大鼠的暴饮暴食是否是由于肝脏能量状态下降的易感性增强所致。(2)确定肥胖倾向大鼠的暴食是否由于肝脏能量状态恢复缓慢所致。(3)研究瘦身大鼠和肥胖大鼠肝细胞代谢刺激转导过程中钙信号的差异。

DESCRIPTION (provided by applicant): Postabsorptive fuel metabolism is an important factor in the control of food intake. Sensors in brain and liver that are sensitive to various metabolic parameters have been implicated in this control. In liver, considerable evidence indicates that changes in energy metabolism produce a stimulus or stimuli that are transduced into a neural signal that carries this metabolic information to the central nervous system for use in controlling food intake. In particular, changes in hepatic ATP content, or some closely related change in liver energy status, generate signals that initiate or terminate feeding behavior under various conditions, such as fasting-refeeding, type I diabetes, and treatment with metabolic inhibitors. Recent studies in this laboratory have revealed that three different animal models of obesity (genetic, dietary and neurological) show reduced hepatic energy status, suggesting that changes in liver energy status are also involved in overeating and the development of obesity. The overall goal of this project is to assess whether and how altered hepatic energy metabolism is a contributing cause of hyperphagia (overeating) that leads to obesity. Some rats overeat and become obese when fed a diet high in fat content (obesity-prone), whereas others of the same strain do not (obesity-resistant). The proposed research will use this diet-induced animal model of obesity because it appears most comparable to the obesity commonly seen in humans. We hypothesize that, during the development of obesity, hyperphagia may be driven at least in part by decreased liver energy status, which is secondary to the redirection of fuels into storage and away from oxidative pathways. Overeating could result from a faster decline in hepatic energy status between meals or a slower recovery in hepatic energy status during and after a meal. The project has three specific aims: (1) Determine whether overeating in obesity prone rats is due to an enhanced susceptibility to reductions in liver energy status. (2) Determine whether overeating in obesity prone rats is due to a slow restoration of liver energy status. (3) Determine whether calcium signaling during metabolic stimulus transduction differs in hepatocytes from lean and obese rats.