LOUISIANA COBRE: P4: MECHANISMS OF AGING-INDUCED LEPTIN RESISTANCE AND OBESITY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 A.具体目标 根据最近研究重点和研究进展的变化、外部咨询委员会的具体建议以及研究部门审查的意见，对COBRE项目的目标进行了修改。 到目前为止，COBRE的工作主要集中在年龄和饮食诱导的瘦素抵抗，以及PTP 1B在下丘脑内诱导瘦素抵抗中的作用。 虽然我们的工作已经确定下丘脑PTP 1B有助于年龄和饮食诱导的瘦素抵抗，但外部咨询委员会表示，将PTP 1B作为瘦素抵抗机制的狭隘关注不太可能导致大量资金。 因此，我们已经修改了该项目，现在重点关注下丘脑和海马中改变的瘦素信号传导对能量稳态和认知功能年龄相关性下降的贡献，特别关注瘦素和氧化应激之间的相互作用。 这是一个新的研究热点，具有重要意义。 修订后的项目列出了四个具体目标： 具体目标1：验证衰老增强高脂饮食（HFD）对大脑瘦素信号传导、代谢和行为的负面影响的假设。 具体目标二：测试老化将损害动物在HFD停止后减少身体肥胖和恢复正常脑瘦素信号传导的能力的假设。 具体目标3：验证瘦素通过NRF 2信号增强抗氧化酶活性来保护下丘脑和海马神经元免受氧化应激的假设。 具体目标4：确定瘦素信号传导和海马和下丘脑区域内的氧化应激之间的功能相互作用。 应当指出，虽然这些目标反映了在以前目标基础上的重点转移，但项目的总体范围仍然非常相似。 也就是说，我们继续对瘦素信号在能量稳态调节中的作用以及衰老和HFD对大脑瘦素信号的负面影响感兴趣。 这些变化主要反映了从关注PTP 1B作为瘦素信号传导的分子介体的转变，更多地转向瘦素信号传导受损对神经元功能的影响以及年龄诱导的与年龄和饮食诱导的氧化应激的相互作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A. Specific Aims The aims of this COBRE project have been amended in response to recent changes in research focus and research progress, specific recommendations from the external advisory committee, and comments from Study Section reviews. To date this COBRE work has focused on age and diet induced leptin resistance, and the role that PTP1B plays in inducing leptin resistance within the hypothalamus. Though our work has established that hypothalamic PTP1B contributes to both age and diet-induced leptin resistance, the external advisory committee indicated that the narrow focus on PTP1B as the mechanism of leptin resistance was not likely to lead to significant funding. Therefore, we have revised the project, which now focuses on the contribution of altered leptin signaling in the hypothalamus and hippocampus to age-related declines in energy homeostasis and cognitive function, with a specific focus on the interaction between leptin and oxidative stress. This represents a novel research focus with substantial significance. The revised project lists four Specific Aims: Specific Aim 1: Test the hypothesis that aging enhances the negative effects of high fat diet (HFD) on brain leptin signaling, metabolism and behavior. Specific Aim 2: Test the hypothesis that aging will impair the ability of the animal to reduce body adiposity and recover normal brain leptin signaling following cessation of a HFD. Specific Aim 3: Test the hypothesis that leptin protects against oxidative stress in hypothalamic and hippocampal neurons by enhancing antioxidant enzyme activity via NRF2 signaling. Specific Aim 4: Determine the functional interaction between leptin signaling and oxidative stress within areas of the hippocampus and hypothalamus. It should be noted that while these Aims reflect a shift in focus based on previous aims, the overall scope of the project remains very similar. Namely, we continue to be interested in the role of leptin signaling in the regulation of energy homeostasis, and the negative impact that both aging and HFDs have on brain leptin signaling. The changes primarily reflect a shift away from a focus on PTP1B as a molecular mediator of leptin signaling, and more toward the impact of impaired leptin signaling on neuron function and the interaction of age-induced with age- and diet-induced oxidative stress.