Role of Variability in SPA in Susceptibility to Obesity

描述(由申请人提供)：肥胖症的治疗仍然有限，成功率很低。目前的治疗方法没有考虑到已知的个体肥胖易感性的差异，这可能是开发成功治疗方法的关键。肥胖的易感性和严重性与自发体力活动(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发展提供生物学基础。为了做到这一点，我们将使用一种新的肥胖易感性差异模型，高活动(HA)和低活动(LA)大鼠。与LA大鼠相比，HA大鼠具有较高的肥胖抵抗能力和较高的增食欲素肽信号强度。食欲素是SPA和能量平衡的关键调节器。我们的总体目标是确定增食欲素参与TO SPA的机制及其与HA/LA大鼠肥胖易感性的相关性。长期以来，关于食欲素的一个假说是它们的功能特化，即下丘脑外侧(LH)的食欲素神经元介导奖赏，而穹隆周围区(PEF)和下丘脑背内侧(DMH)的神经元则介导觉醒。目的1将确定哪些增食欲素神经元亚群(LH或PEF/DMH)与HA/LA表型更相关。我们将在这些区域敲除和过度表达食欲素，以测试它们对SPA的必要性或充分性。接下来，我们将重点介绍通过嘴促黄体生成素(RLH)传递的食欲素信号。这一途径调节SPA的增加，可能是HA表型表达的关键。目的2确定促黄体生成素增食素信号与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，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，影响摄食和SPA。抑制NAcSh GABA能传出能增加在LA中注射增食欲素引起的SPA，但对HA大鼠无影响。AIM 3将研究HA/LA表型中NAcSh和RLH的相互作用。我们将确定在HA大鼠中是否存在RLH和NAcSh食欲素信号的联合作用，NAcSh操作后的摄食反应在HA/LA大鼠之间是否不同，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大鼠之间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，并加强肥胖的治疗方法。

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.