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。子项目及 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。 肥胖症是美国的一个严重健康问题，在过去十年中肥胖症的患病率显著增加。衰老导致肥胖症的发生，随着人类达到成熟，肥胖症的患病率明显增加。衰老也与对肥胖信号瘦素的敏感性降低有关。考虑到瘦素信号传导对于体重和葡萄糖代谢的适当调节是必要的，这些观察结果支持瘦素敏感性降低导致肥胖风险随年龄增加的模型。目前发表的研究主要集中在瘦素信号在先进的年龄，很少有研究解决的细胞机制介导的初步发展的瘦素抵抗的个人达到成熟。申请人产生的初步数据表明，下丘脑蛋白酪氨酸磷酸酶1B（PTP 1B）水平随年龄增加，下丘脑信号传导的急性药理学阻断恢复了成熟的瘦素抵抗大鼠的瘦素敏感性。考虑到已知PTP 1B抑制瘦素信号传导，这些观察结果支持以下假设，即衰老诱导的下丘脑PTP 1B增加抑制瘦素参与瘦素敏感神经元内特定信号传导组分的能力。 目前的提议将定义衰老诱导的PTP 1B增加的生理和细胞机制，并测试PTP 1B是否也有助于下丘脑外区域的瘦素抵抗。该建议的首要假设是，衰老诱导的PTP 1B增加独立于身体肥胖的增加而发生，并且这些局部增加导致限定脑区域内的瘦素抵抗。通过确定年龄相关的PTP 1B增加是否需要增加身体肥胖，胰岛素或瘦素是否局部作用于增加PTP 1B，以及 PTP 1B的增加是否与下丘脑外区域衰老诱导的瘦素抵抗有关。这一提议描述了一种新的机制，解释衰老诱导的瘦素抵抗，并有可能增加我们对使个体易患肥胖症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.