METABOLIC CONTROL OF FEEDING BEHAVIOR

描述（由申请人提供）：吸收后的燃料代谢是控制食物摄入的重要因素。大脑和肝脏中对各种代谢参数敏感的传感器参与了这种控制。在肝脏中，大量证据表明，能量代谢的变化产生一种或多种刺激，这些刺激被转导成神经信号，将这种代谢信息传递给中枢神经系统，用于控制食物摄入。特别是肝脏ATP含量的变化，或一些密切相关的肝脏能量状态的变化，在各种情况下产生启动或终止摄食行为的信号，如禁食-再摄食、I型糖尿病和使用代谢抑制剂治疗。本实验室最近的研究表明，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与暴饮暴食和肥胖的发生有关。该项目的总体目标是评估肝脏能量代谢的改变是否以及如何导致导致肥胖的贪食（暴饮暴食）。当喂食高脂肪食物时，一些老鼠会吃得过多而变得肥胖（容易肥胖），而同一品系的其他老鼠则不会（不易肥胖）。拟议中的研究将使用这种由饮食引起的动物肥胖模型，因为它似乎与人类中常见的肥胖最相似。我们假设，在肥胖的发展过程中，暴饮暴食可能至少部分是由肝脏能量状态下降所驱动的，而肝脏能量状态的下降是继发于燃料从氧化途径转向储存的过程。暴饮暴食可能是由于两餐之间肝能状态下降得更快，或在餐中和餐后肝能状态恢复得更慢。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由于肝脏能量状态降低的易感性增强。(2)确定肥胖易感大鼠的暴饮暴食是否由于肝脏能量状态恢复缓慢。(3)确定瘦大鼠和肥胖大鼠肝细胞代谢刺激转导过程中的钙信号传导是否不同。

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.