Interactions between neuronal networks that regulate food intake and body weight

描述（由申请人提供）：流行病学研究表明，超重儿童的食物摄入量增加和肥胖的模式预示着成人肥胖，因此迫切需要新的方法来对抗儿童的“肥胖流行病”。过去几十年的研究工作已经确定了调节食物摄入和体重的神经元回路的许多信号和细胞成分;然而，这些研究中的绝大多数都是在成熟动物中进行的。基因功能破坏或出生时神经元消融导致的轻度表型凸显了这样一个事实：调节能量稳态的神经元回路在幼年动物中具有非凡的补偿能力。下丘脑瘦素抵抗（LeprHYP）的遗传模型提供了一个系统，以探索这些“补偿”功能是否可以利用来改善代谢表型在一个关键时期的发展电路调节能量消耗和肥胖。LeprHYP小鼠表现出早发性食欲过盛和肥胖;然而，它们从8周龄起保持稳定的肥胖水平。这些发现支持了这样的观点，即在年轻的LeprHYP小鼠中建立的代谢表型的基线随着成熟而得到保护。为了探索幼年LeprHYP小鼠中改变的代谢参数是否会在成年小鼠中得到保护，从断奶到10周龄，将LeprHYP小鼠配对喂养至对照组的摄入。在配对喂养期间，肥胖减少了~20%，但更重要的是，这种较低的肥胖水平在整个成年期稳定地保持。这些发现提出了一种可能性，即啮齿动物的断奶后时期代表了发育的关键时期，在此期间代谢表型响应其营养/激素环境而发展。 拟议研究的目标是确定代谢表型的时间（目标1），生理（目标2）和空间（目标3）相关的推定的“关键时期的发展”。敏感期的时间窗口将通过减少配对喂养的持续时间来更精确地限定（目标1，实验2）。1）。为了检查推定的关键期的分子等同物是否类似于在感觉回路中操作的分子等同物，将评估GABAa受体激动剂过早启动关键期的发作的能力（目的1，实验2）。2）。目标2中的分析旨在定义与成年人持续存在的配对喂养相关的生理适应，因为调节这些表型的回路可能代表系统可塑性的重要来源。目标3中的研究将检查下丘脑瘦素感知回路如何与其他神经元回路相互作用以调节代谢表型。为了检查与下丘脑胰岛素感测回路的相互作用，将LeprHYP与胰岛素受体（Insr）的floxed等位基因杂交（Aim 3，Exp. 1）。将在具有瘦素信号的泛神经元破坏的小鼠中检查下丘脑外瘦素感应神经元对通过配对喂养实现的肥胖减少和/或其在成年人中的维持的贡献（目的3，实验2）。 公共卫生相关性：大多数关于大脑中调节进食和体重的回路的研究都是在成年人中进行的。拟议的实验旨在确定回路的组成部分，这些组成部分对于在年轻动物中建立体脂百分比和代谢率的早期模式至关重要，因为它们可能对此时的干预措施更敏感。这些知识可能会导致对抗儿童肥胖的新策略。

DESCRIPTION (provided by applicant): Epidemiological studies have shown that patterns of increased food intake and adiposity in overweight children are predictive of adult obesity, and thus lend urgency to the need for novel approaches to combat the "obesity epidemic" in children. Research efforts in the past several decades have identified many signals and cellular components of neuronal circuits that regulate food intake and body weight; however, the vast majority of these studies have been performed in mature animals. Mild phenotypes resulting from disruptions of gene function or neuronal ablations from birth highlight the fact that neuronal circuits regulating energy homeostasis have an extraordinary compensatory capacity in young animals. A genetic model of hypothalamic leptin resistance (LeprHYP) provides a system to explore whether these "compensatory" functions can be harnessed to improve metabolic phenotypes during a critical period of development for circuits regulating energy expenditure and adiposity. LeprHYP mice exhibit early-onset hyperphagia and obesity; however, they maintain stable levels of adiposity from 8 weeks of age. These findings support the idea that baselines for metabolic phenotypes that are established in young LeprHYP mice are defended with maturity. To explore whether altered metabolic parameters in young LeprHYP mice would be defended in adults, LeprHYP mice were pair-fed to the intake of controls from weaning through 10 weeks of age. Adiposity was reduced by ~20% during the pair- feeding, but more importantly, this lower level of adiposity was stably maintained throughout adulthood. These findings raised the possibility that the post-weaning period in rodents represents a critical period of development during which metabolic phenotypes develop in response to their nutrient/hormonal environment. The goal of the proposed studies is to define the temporal (Aim 1), physiological (Aim 2) and spatial (Aim 3) correlates of a putative "critical period of development" for metabolic phenotypes. The time window of the sensitive period will be more precisely defined by reducing the duration of the pair-feeding (Aim 1, Exp. 1). To examine whether the molecular predicates of the putative critical period are similar to those that operate in sensory circuits, the ability of GABAA receptor agonists to prematurely initiate the onset of the critical period will be assessed (Aim 1, Exp. 2). Analyses in Aim 2 are designed to define the physiological adaptations associated with pair-feeding that persist in adults, as the circuits regulating these phenotypes likely represent an important source of plasticity in the system. Studies in Aim 3 will examine how hypothalamic leptin- sensing circuits interact with other neuronal circuits to regulate metabolic phenotypes. To examine interactions with hypothalamic insulin-sensing circuits, LeprHYP will be crossed to a floxed allele of insulin receptor (Insr) (Aim 3, Exp. 1). The contribution of extra-hypothalamic leptin-sensing neurons to either the reduction in adiposity achieved by pair-feeding and/or its maintenance in adults will be examined in mice with a pan- neuronal disruption of leptin signals (Aim 3, Exp 2). PUBLIC HEALTH RELEVANCE: Most studies of circuits in the brain that regulate feeding and body weight have been performed in adults. The proposed experiments are designed to identify the components of the circuits that are critical for establishing early patterns of percent body fat and metabolic rate in young animals, as they are likely to be more responsive to interventions at this time. This knowledge could lead to novel strategies to combat childhood obesity.