Role of Variability in SPA in Susceptibility to Obesity

SPA 变异在肥胖易感性中的作用

基本信息

批准号：
9211311
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-09-30
项目状态：
已结题

项目摘要

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率较低。目前的治疗方法并未考虑到个体肥胖易感性的已知差异，而这可能是开发成功治疗方法的关键。肥胖的易感性和严重程度与自发体力活动（SPA）的个体差异有关。我们的长期目标是为个性化肥胖疗法的开发提供生物学基础。为此，我们将使用一种新的肥胖易感性差异模型，即高活动 (HA) 和低活动 (LA) 大鼠。 HA 大鼠比 LA 大鼠具有抗肥胖能力，并且食欲素肽信号传导更强。食欲素是 SPA 和能量平衡的关键调节剂。我们的总体目标是确定食欲素参与 SPA 的机制及其与 HA/LA 大鼠模型中肥胖易感性的相关性。关于食欲素的一个长期存在的假设是它们的功能专门化，该假设认为下丘脑外侧（LH）中的食欲素神经元介导奖励，而下丘脑周围区域（PeF）和背内侧下丘脑（DMH）中的神经元介导唤醒。目标 1 将确定哪些食欲素神经元亚群（LH 或 PeF/DMH）与 HA/LA 表型更相关。我们将在这些区域敲低和过度表达食欲素，以测试它们对于 SPA 的必要性或充分性。接下来，我们将重点关注通过喙侧 LH (rLH) 的食欲素信号传导。该途径介导 SPA 的增加，可能是 HA 表型表达的关键。目标 2 将确定 rLH 食欲素信号传导与 HA/LA 大鼠肥胖易感性的相关性。我们将确定肥胖如何影响 HA/LA 大鼠的食欲素 rLH 信号传导，以及阻断 rLH 中的食欲素反应是否会增加 HA 大鼠的肥胖易感性。接下来，我们将研究 rLH 和伏隔核壳 (NAcSh) 之间的相互作用。 NAcSh 与食欲素神经元相互作用，影响进食和 SPA。抑制 NAcSh GABA 能传出神经会增加 LA 大鼠 rLH 中注射食欲素引起的 SPA，但在 HA 大鼠中则不然。目标 3 将研究 HA/LA 表型中 NAcSh 和 rLH 的相互作用。我们将确定 HA 大鼠中 rLH 和 NAcSh 食欲素信号传导是否存在联合效应，HA/LA 大鼠操纵 NAcSh 后的进食反应是否不同，并确定 NAcSh 和 rLH 食欲素反应神经元之间的神经解剖学联系。这些研究将填补食欲素神经回路在调节 HA 和 LA 大鼠表型差异方面的知识空白，这将提高我们对个体肥胖易感性背后的大脑机制的理解，并增强肥胖的治疗方法。