This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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, andwhether 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.
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