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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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科审查的意见，对Cobre项目的目标进行了修改。到目前为止，Cobre的这项工作主要集中在年龄和饮食诱导的瘦素抵抗，以及PTP1B在诱导下丘脑内的瘦素抵抗中所起的作用。虽然我们的工作已经确定下丘脑PTP1B与年龄和饮食诱导的瘦素抵抗有关，但外部咨询委员会指出，将PTP1B作为瘦素抵抗的机制进行狭隘的关注不太可能导致大量资金投入。因此，我们对该项目进行了修订，现在重点关注下丘脑和海马体中瘦素信号的改变对与年龄相关的能量稳态和认知功能下降的贡献，并特别关注瘦素和氧化应激之间的相互作用。这代表了一个具有重大意义的新的研究焦点。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、代谢和行为的负面影响的假说。 具体目标2：验证衰老将削弱动物在停止HFD后减少身体肥胖和恢复正常脑瘦素信号的能力的假设。 具体目标3：验证瘦素通过NRF2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：确定瘦素信号与海马区和下丘脑区氧化应激之间的功能相互作用。 应当指出的是，虽然这些目标反映了在以往目标的基础上重点的转移，但项目的总体范围仍然非常相似。也就是说，我们仍然感兴趣的是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。这些变化主要反映了从关注PTP1B作为瘦素信号的分子介质转向关注瘦素信号受损对神经元功能的影响，以及AGE诱导的AGE与AGE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.