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，超重儿童食物摄入增加和肥胖的模式可以预测成人肥胖，因此迫切需要新的方法来对抗儿童中的“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回路的许多信号和细胞成分；然而，这些研究绝大多数是在成熟动物身上进行的。由基因功能破坏或出生时神经元消融引起的轻度表型突出了一个事实，即调节能量稳态的神经回路在幼龄动物中具有非凡的代偿能力。下丘脑瘦素抵抗（LeprHYP）的遗传模型为探索这些“代偿”功能是否可以在调节能量消耗和肥胖的回路发育的关键时期改善代谢表型提供了一个系统。麻风小鼠表现为早发性贪食和肥胖；然而，他们从8周龄开始保持稳定的肥胖水平。这些发现支持了这样一种观点，即在年轻麻风小鼠中建立的代谢表型基线随着成熟而得到保护。为了探索成年LeprHYP小鼠代谢参数的改变是否会在成年LeprHYP小鼠中得到保护，从断奶到10周龄，LeprHYP小鼠与对照组配对喂养。在配对饲养期间，肥胖减少了约20%，但更重要的是，这种低水平的肥胖在整个成年期都保持稳定。这些发现提出了一种可能性，即啮齿动物断奶后的时期代表了一个关键的发育时期，在此期间，代谢表型根据其营养/激素环境而发育。拟议研究的目标是定义代谢表型的假定“发育关键时期”的时间（目标1）、生理（目标2）和空间（目标3）相关性。通过减少成对进食的持续时间，可以更精确地定义敏感期的时间窗口（目的1，实验1）。为了检查假定的临界期的分子谓词是否与感觉回路中的分子谓词相似，将评估GABAA受体激动剂过早启动临界期的能力（目的1，实验2）。Aim 2中的分析旨在定义与成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了系统中可塑性的重要来源。Aim 3的研究将研究下丘脑瘦素感应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应回路的相互作用，LeprHYP将与胰岛素受体（Insr）的一个floxed等位基因交叉（目的3，实验1）。下丘脑外瘦素感知神经元对通过配对喂养实现的肥胖减少和/或维持成人肥胖的贡献将在瘦素信号泛神经元破坏的小鼠中进行研究（目的3，实验2）。

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.