CNS NFkappaB Regulation of Glucose Homeostasis

描述(申请人提供)：肥胖症在三分之一的美国成年人和儿童中普遍存在，每年给美国医疗保健系统造成数十亿美元的损失。肥胖对患者的主要影响是与肥胖相关的并发症的发展，如2型糖尿病(T2 DM)。鉴于肥胖给社会带来的巨大代价，以及这些疾病对患者的影响，建立肥胖症与T2 DM之间的联系对于有效治疗和降低T2 DM的患病率至关重要。肥胖和2型糖尿病之间的可能机制之一是通过炎症途径。越来越多的证据表明，中枢神经系统对调节血糖稳态的激素和营养物质有反应，而这一系统的失调可能与核因子B的激活有关。然而，这一通路对外周代谢过程的潜在中枢调节作用尚未被研究。在这项提案中，西斯利博士将重点研究一种特定的脑部炎症途径--核因子？B--对血糖稳态的影响。她的初步数据显示，单剂量的核因子？B抑制剂能够改善糖耐量。她建议的具体目标将通过急性抑制研究来检验中枢神经系统抑制核因子B途径对葡萄糖稳态的抑制之间的机制联系。她还将研究中枢神经系统核因子B抑制对周围组织炎症标志物的影响。这一导师奖学金的主要目标是推动西斯利博士在追求独立研究事业的道路上向前迈进。 公共卫生相关性：拟议的研究有望阐明中枢神经系统核因子B在调节血糖稳态和外周炎症中的作用。这一贡献意义重大，因为它将为肥胖症和T2 DM之间的联系提供新的信息，并可能确定新的潜在治疗方案，以减轻T2 DM的社会负担。

DESCRIPTION (provided by applicant): Obesity is prevalent in one third of American adults and children and costs the American health care system billions of dollars yearly. The major impact of obesity on patients is the development of obesity-related comorbidities, such as type 2 diabetes mellitus (T2DM). Given the extensive cost to society, as well as the impact of these conditions on patients, establishing the link between obesity and T2DM is paramount to effectively treating and decreasing the prevalence of T2DM. One of the possible mechanisms linking obesity and T2DM is through inflammatory pathways. Accumulating evidence indicates that the CNS is responsive to hormones and nutrients regulating glucose homeostasis and that dysregulation of this system may occur with NF?B activation. However, the potential CNS regulation of this pathway on peripheral metabolic processes has not been studied. In this proposal, Dr. Sisley will focus on the effect of one specific brain inflammatory pathway, NF?B, on glucose homeostasis. Her preliminary data have revealed the ability of a single dose of an NF?B inhibitor to improve glucose tolerance. The specific aims of her proposal will examine the mechanistic link between CNS inhibition of the NF?B pathway on glucose homeostasis using acute inhibition studies. She will also investigate the effect of CNS NF?B inhibition on inflammatory markers in peripheral tissues. The primary goal of this mentored fellowship award is to advance Dr. Sisley forward in her pursuit of an independent research career. PUBLIC HEALTH RELEVANCE: The proposed studies are expected to elucidate the role of CNS NF?B in the regulation of glucose homeostasis and peripheral inflammation. This contribution is significant because it will provide new information on the linkage between obesity and T2DM and may identify new potential therapeutic options to alleviate the societal burden of T2DM.