Role of Variability in SPA in Susceptibility to Obesity

SPA 变异在肥胖易感性中的作用

• 批准号: 8998020
• 负责人: CATHERINE M KOTZ
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998020
• 关键词: Accounting; Affect; Area; Arousal; Automobile Driving; Behavior; Behavioral; Biochemical; Biological; Biological Assay; Brain; Data; Development; Diet; Eating; Energy Metabolism; Goals; Health; Human; Hypothalamic structure; Individual; Individual Differences; Injection of therapeutic agent; Intake; Knowledge; Lateral; Link; Mediating; Modeling; Movement; Muscimol; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Pathway interactions; Peptides; Phenotype; Physical activity; Predisposition; Rattus; Resistance; Rewards; Rodent; Role; Severities; Signal Transduction; Site; System; Testing; Therapeutic; Variant; Virus; base; behavioral response; energy balance; feeding; hypocretin; improved; innovation; knock-down; mRNA Expression; neural circuit; novel; obesity treatment; obesogenic; orexin A; overexpression; prevent; relating to nervous system; response; small hairpin RNA; success

DESCRIPTION (provided by applicant): Treatments for obesity remain limited and with low success. Current therapies do not account for known differences in individual obesity susceptibility, which might be key for developing successful treatments. Susceptibility and severity to obesity are linked to individual differences in spontaneous physical activity (SPA). Our long-term goal is to provide the biological basis for development of personalized obesity therapies. To do this, we will use a novel model of differential susceptibility to obesity, the hig activity (HA) and low activity (LA) rats. HA rats are obesity resistant and higher signaling by orexin peptides than LA rats. The orexins are key modulators of SPA and energy balance. Our overall goal is to define the mechanisms underlying orexin involvement in to SPA and their relevance to obesity susceptibility in the HA/LA rat model. A long-standing hypothesis about the orexins is their functional specialization, which proposes that orexin neurons in the lateral hypothalamus (LH) mediate reward, while neurons in the perifornical area (PeF) and dorsomedial hypothalamus (DMH) mediate arousal. Aim 1 will determine which orexin neuron subpopulations (LH or PeF/DMH) are more relevant for the HA/LA phenotype. We will knock- down and over-express orexins in these areas to test their necessity or sufficiency for SPA in. Next, we will focus on orexin signaling through rostral LH (rLH). This pathway mediates increases in SPA and may be key for expression of the HA phenotype. Aim 2 will determine the relevance of rLH orexin signaling to obesity susceptibility in HA/LA rats. We will determine how obesity affects orexin rLH signaling in HA/LA rats and if blocking orexin responses in rLH increases obesity susceptibility in HA rats. Next, we will study interactions between rLH and nucleus accumbens shell (NAcSh). NAcSh interacts with orexin neurons to affect feeding and SPA. Inhibition of NAcSh GABAergic efferents increases SPA caused by orexin injection in rLH in LA, but not in HA rats. Aim 3 will study NAcSh and rLH interactions in the HA/LA phenotype. We will determine if there is a combined effect of rLH and NAcSh orexin signaling in HA rats, whether feeding responses after manipulation of NAcSh are different between HA/LA rats and define the neuroanatomical connections between NAcSh and rLH orexin-responsive neurons. These studies will fill the gap in knowledge of orexin neural circuitry in mediating phenotypic differences between HA and LA rats, which will improve our understanding of brain mechanisms underlying individual obesity susceptibility and enhance therapeutic approaches to obesity.

描述（由申请人提供）：肥胖症的治疗仍然有限且成功较低。当前的疗法没有说明个体肥胖易感性的已知差异，这可能是开发成功治疗的关键。对肥胖症的敏感性和严重程度与自发体育锻炼（SPA）的个体差异有关。我们的长期目标是为开发个性化肥胖疗法的生物学基础。为此，我们将使用一种新型的模型，具有对肥胖症，HIG活性（HA）和低活动（LA）大鼠的差异敏感性的新模型。与LA大鼠相比，HA大鼠是肥胖性耐肥胖和更高的信号传导。 Orexins是水疗和能量平衡的关键调节剂。 我们的总体目标是定义Orexin参与水疗中心的机制及其与HA/LA大鼠模型中肥胖易感性的相关性。关于Orexins的长期假设是它们的功能专业化，该假设提出下丘脑（LH）中的Orexin神经元介导了奖励，而神经元（PEF）（PEF）和背侧性下丘脑（DMH）介导了神经元。 AIM 1将确定哪种Orexin神经元亚群（LH或PEF/DMH）与HA/LA表型更相关。我们将在这些区域中敲低和过表达的甲氧胺，以测试其对水疗中心的必要性或足够的水平。接下来，我们将通过Rostral LH（RLH）重点关注Orexin信号。该途径介导水疗中心的增加，可能是表达HA表型的关键。 AIM 2将确定RLH Orexin信号传导与HA/LA大鼠肥胖敏感性的相关性。我们将确定肥胖症如何影响HA/LA大鼠中的Orexin RLH信号传导，以及RLH中的Orexin反应是否会增加HA大鼠的肥胖症的敏感性。接下来，我们将研究RLH和伏隔核之间的相互作用（NACSH）。 NACSH与Orexin神经元相互作用，以影响喂养和水疗中心。 Nacsh Gabaergic Ferrents的抑制会增加由LA中的RLH注射甲的水疗中心，但在HA大鼠中不增加。 AIM 3将研究HA/LA表型中的NACSH和RLH相互作用。我们将确定HA大鼠中RLH和NACSH Orexin信号传导的综合作用，NACSH操纵后的喂养反应是否有所不同，并定义NACSH和RLH或RLH或RLH或RLH或RLH或RLH或RLH反应性神经元之间。 这些研究将填补OREXIN神经回路的知识差异，以介导HA和LA RAT之间的表型差异，这将提高我们对个体肥胖易感性的脑机制的理解并增强肥胖症的治疗方法。