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。 在美国，肥胖是一个严重的健康问题，在过去的十年里，肥胖症的流行率显著上升。老龄化导致了肥胖的发生，随着人类达到成熟期，肥胖的患病率明显增加。衰老还与肥胖信号瘦素的敏感度降低有关。考虑到瘦素信号对于适当调节体重和葡萄糖代谢是必要的，这些观察结果支持这样一个模型，即瘦素敏感性的降低导致肥胖风险随着年龄的增加而增加。目前发表的研究主要集中在高龄瘦素信号转导，很少有研究涉及个体成熟后瘦素抵抗最初发展的细胞机制。申请人提供的初步数据表明，下丘脑蛋白酪氨酸磷酸酶1B(PTP1B)水平随着年龄的增长而增加，急性药物阻断下丘脑信号可以恢复成熟的瘦素抵抗大鼠的瘦素敏感性。考虑到PTP1B已知可抑制瘦素信号，这些观察结果支持一种假说，即衰老导致下丘脑PTP1B的增加抑制了瘦素与瘦素敏感神经元中特定信号成分的结合能力。 目前的提案将确定衰老导致PTP1B增加的生理和细胞机制，并测试PTP1B是否也有助于下丘脑以外区域的瘦素抵抗。这一建议的主要假设是，衰老导致的PTP1B增加独立于身体肥胖的增加，并且这些局部增加导致特定脑区内的瘦素抵抗。这一假说将通过确定与年龄相关的PTP1B增加是否需要增加身体脂肪来检验，胰岛素或瘦素是否局部作用于增加PTP1B，以及 PTP1B的增加是否与衰老诱导的下丘脑以外区域的瘦素抵抗有关。这项建议描述了一种新的机制来解释衰老诱导的瘦素抵抗，并有可能增加我们对使个人容易肥胖的特定信号事件的理解。

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. Obesity is a serious health issue within the US, with the prevalence of obesity increasing markedly over the past decade. Aging contributes to the incidence of obesity, with humans exhibiting a distinct increase in the prevalence of obesity as they reach maturity. Aging is also associated with a reduced sensitivity to the adiposity signal leptin. Considering that leptin signaling is necessary for the appropriate regulation of body weight and glucose metabolism, these observations support a model in which decreases in leptin sensitivity contribute to the increased risk for obesity with aging. Currently published studies primarily focus on leptin signaling at advanced ages, and few studies address the cellular mechanisms mediating the initial development of leptin resistance as individuals reach maturity. Preliminary data generated by the applicant indicates that hypothalamic protein tyrosine phosphatase 1B (PTP1B) levels are increased with age, and that acute pharmacological blockade of hypothalamic signaling restores leptin sensitivity in mature, leptin resistant rats. Considering that PTP1B is known to inhibit leptin signaling, these observation support a hypothesis in which aging-induced increases in hypothalamic PTP1B inhibit leptin's ability to engage specific signaling components within leptin-sensitive neurons. The current proposal will define the physiological and cellular mechanisms underlying aging-induced increases in PTP1B, and test whether PTP1B also contributes to leptin resistance in areas outside the hypothalamus. The overarching hypothesis of this proposal is that aging-induced increases in PTP1B occur independently from increases in body adiposity, and that these local increases result in leptin resistance within defined brain areas. This hypothesis will be tested by determining whether age-related increases in PTP1B require increased body adiposity, whether insulin or leptin act locally to increase PTP1B, and whether increases in PTP1B are associated with aging-induced leptin resistance in areas outside the hypothalamus. This proposal describes a novel mechanism explaining aging-induced leptin resistance, and has the potential to increase our understanding of the specific signaling events that predispose individuals to obesity.