Interactions between neuronal networks that regulate food intake and body weight

调节食物摄入和体重的神经网络之间的相互作用

• 批准号: 8105548
• 负责人: Lori M Zeltser
• 金额: $ 33.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-26 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105548
• 关键词: Ablation; Adipose tissue; Adult; Age; Agonist; Alleles; Birth; Body Composition; Body Weight; Body fat; Brain; Brown Fat; Child; Development; Diet; Eating; Energy Metabolism; Environment; Epidemic; Epidemiologic Studies; Exhibits; Exposure to; Fatty acid glycerol esters; GABA Agonists; Gene Expression; Genetic Models; Goals; Heart; Homeostasis; Hormonal; Human; Hyperphagia; Hypothalamic structure; Indirect Calorimetry; Insulin; Insulin Receptor; Intake; Intervention; Knowledge; Laboratories; Lead; Length; Leptin; Leptin resistance; Life; Maintenance; Measures; Medical; Metabolic; Molecular; Molecular Profiling; Motor Activity; Mus; Neuron-Specific Enolase; Neurons; Nutrient; Nutritional; Obesity; Outcome; Overweight; Oxygen Consumption; Pattern; Phenotype; Physiological; Physiological Adaptation; Publishing; Research; Risk; Rodent; Sensory; Signal Transduction; Source; Sympathetic Nervous System; Synapses; System; Time; Visceral; Weaning; combat; critical period; design; early childhood; early onset; energy balance; feeding; food restriction; gene function; hypothalamic-pituitary-adrenal axis; improved; infancy; insight; insulin signaling; juvenile animal; leptin receptor; male; mature animal; novel strategies; obesity in children; pituitary thyroid axis; programs; receptor; research study; response; subcutaneous

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.

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和肥胖的模式可以预测成人肥胖，因此使需要新颖的方法来应对儿童的“肥胖流行”。在过去的几十年中，研究工作确定了调节食物摄入和体重的神经元电路的许多信号和细胞成分。但是，这些研究的绝大多数是在成熟的动物中进行的。由基因功能或神经元消融的中断引起的轻度表型突出了调节能量稳态的神经元电路的事实，在年轻动物中具有非凡的补偿能力。下丘脑瘦素耐药性（LEPRHYP）的遗传模型提供了一个系统来探索这些“补偿性”功能是否可以利用这些“补偿性”功能来改善代谢表型，以调节调节能量消耗和肥胖的电路的关键时期。 LEPRHYP小鼠表现出早发的心和肥胖；但是，它们从8周龄开始保持稳定的肥胖水平。这些发现支持这样一种观念，即在年轻的LEPRHYP小鼠中建立的代谢表型基准是成熟的。为了探索成人年轻的LEPRHYP小鼠的代谢参数是否改变，LEPRHYP小鼠对从断奶到10周龄的对照组合成对。在配对期间，肥胖降低了约20％，但更重要的是，整个成年期稳定地保持了这种较低的肥胖水平。这些发现提出了一种可能性，即啮齿动物的断奶后期代表了一个关键的发育时期，在此期间，代谢表型响应其营养/荷尔蒙环境而发展。 拟议的研究的目的是定义时间（AIM 1），生理（AIM 2）和空间（AIM 3）相关的代谢表型的“关键发展时期”的相关性。敏感周期的时间窗口将通过减少配对的持续时间（AIM 1，Exp。1）来精确定义。为了检查假定关键时期的分子谓词是否与在感觉回路中运行的分子谓词相似，将评估GABAA受体激动剂过早启动关键时期开始的能力（AIM 1，Exp。2）。 AIM 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性，因为调节这些表型的电路可能代表了系统中可塑性的重要来源。 AIM 3中的研究将研究下丘脑瘦素感应电路如何与其他神经元电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电路的相互作用，LEPRHYP将被交叉到胰岛素受体（INSR）的flox等位基因（AIM 3，Exp。1）。在成年人的喂养和/或其在成年人中维持的肥胖性降低和/或在成年人中的维持，将在小鼠中检查瘦素信号的小鼠（AIM 3，EXP 2），对成年人的肥胖和/或其在成年人中的维持的降低（AIM 3，EXP 2）。 公共卫生相关性：大脑在大脑中调节喂养和体重的大多数研究是在成年人中进行的。所提出的实验旨在确定电路的组成部分，这些电路对于建立年轻动物的身体脂肪和代谢率百分比的早期模式至关重要，因为它们目前可能对干预措施更敏感。这些知识可能导致打击儿童肥胖症的新型策略。