Interactions between neuronal networks that regulate food intake and body weight

描述(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是成人肥胖的预测，因此迫切需要新的方法来抗击儿童中的“肥胖流行病”。在过去的几十年里，研究工作已经确定了调节食物摄入量和体重的神经元回路的许多信号和细胞组件；然而，这些研究中的绝大多数都是在成熟动物身上进行的。从出生起，由于基因功能中断或神经元消融而导致的轻微表型突出了这样一个事实，即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。下丘脑瘦素抵抗的遗传模型(LeprHYP)提供了一个系统，以探索在调节能量消耗和肥胖的回路发育的关键时期，是否可以利用这些“代偿”功能来改善代谢表型。LeprHYP小鼠表现出早发性的吞噬和肥胖；然而，它们从8周大开始就保持了稳定的肥胖水平。这些发现支持这样一种观点，即在幼年LeprHYP小鼠中建立的代谢表型基线在成熟后得到保护。为了探索在幼年LeprHYP小鼠身上改变的代谢参数是否会在成年鼠中得到保护，从断奶到10周大的LeprHYP小鼠被配对喂养到对照组。在配对喂养期间，肥胖率降低了约20%，但更重要的是，这种较低的肥胖率在成年后一直保持稳定。这些发现提出了一种可能性，即啮齿动物的断奶后阶段是发育的关键时期，在此期间代谢表型会随着其营养/激素环境的变化而发展。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)相关假定的“发育关键期”。通过缩短配对喂养的持续时间，将更准确地确定敏感期的时间窗口(目标1，实验。1)。为了检验假定的临界期的分子谓词是否类似于那些在感觉回路中工作的分子谓词，将评估GABAA受体激动剂过早启动临界期的能力(目标1，实验。2)。目标2中的分析旨在定义与成年性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着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觉回路如何与其他神经元回路相互作用来调节代谢表型。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)的一个等位基因杂交(目标3，实验。1)。下丘脑外的瘦素感觉神经元对通过配对喂养和/或在成人中维持肥胖所做的贡献将在瘦素信号泛神经元中断的小鼠身上进行检验(目标3，实验2)。 与公共健康相关：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身上进行的。拟议的实验旨在确定对建立幼年动物体内脂肪百分比和代谢率的早期模式至关重要的回路组件，因为它们可能在这个时候对干预更敏感。这些知识可能会导致对抗儿童肥胖症的新策略。

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.