Hypothalamic Glucoregulation in Aging Rodents by fMRI

功能磁共振成像对衰老啮齿动物下丘脑血糖的调节作用

• 批准号: 6399941
• 负责人: JIA-HONG GAO
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399941
• 关键词: age difference; aging; animal old age; bioimaging /biomedical imaging; biological models; blood chemistry; blood glucose; brain imaging /visualization /scanning; dietary restriction; functional magnetic resonance imaging; glucose metabolism; hypothalamus; intraperitoneal injections; laboratory mouse; laboratory rat; male; mature animal; nutrition of aging; nutrition related tag

Aging is a significant cause of morbidity, mortality, and health-care costs in the United States and has associations with diabetes and atherosclerosis. Evidence documenting the anti-aging effect of dietary restriction (DR) exists in a wide variety of laboratory animals. Chronically lowered plasma glucose levels in mice, rats and non-human primates of different ages and using a variety of DR regimens have also been clearly demonstrated. Indeed, it has been suggested that lowered plasma glucose may be an important component of the mechanism by which DR retards aging. Further, the extremely crucial role that the hypothalamus plays in processes like feeding and drinking and its intimate involvement in glucoregulation are well known. However, the in vivo specificity and mechanism responsible for the anti-aging action of decreased plasma glucose following DR still remains unknown. Our overall long-term goal is to understand the hypothalamic mechanism(s) accountable for the decreased plasma glucose following DR and the development of effective preventive and therapeutic anti-aging strategies from the knowledge so gained. The objective of this particular application is to monitor in vivo alterations in glucose metabolism of the hypothalamus with aging and their reversal with DR, using functional magnetic resonance imaging (fMRI). The central hypothesis is that aging alters hypothalamic glucoregulation and that DR retards this age-associated change. Data obtained in our earlier study showed that DR lowers plasma glucose levels throughout the course of the day and over the lifespan of rats. The rationale that underlies the proposed research is that, once knowledge of the hypothalamic response is obtained in diet restricted rats with fMRI, the mechanism that is responsible for this can be subsequently determined. We are uniquely well prepared to undertake the proposed project, as our team's research has already yielded novel observations concerning the effects of DR in rats and has also been successful in demonstrating the in vivo hypothalamic fMRI response (signal intensity change which is a reflection of changes in basal blood flow, blood volume, and blood oxygenation associated with underlying neural activity) following glucose administration in both humans and rats. The central hypothesis will be tested and the objective of this application accomplished by pursuing the following specific aims: (a) To determine if glucose metabolism in the rat hypothalamus is altered with aging and whether DR reverses it; and (b) To determine if these age-related changes can be detected in mice so as to be able to use transgenic models in the future. The proposed work is novel and innovative. and is expected to demonstrate that there are significant alterations with aging, in the normal fMRI hypothalamic response induced by intraperitoneal glucose administration. Such outcomes will have a significant impact on our understanding of glucoregulation in DR. Further, they will be extremely valuable in investigating the effects of DR in transgenic models of mice in the future. Finally, the proposed research is expected to make fundamental new contributions to aging research and can eventually be expected to reduce the complications associated with aging.

在美国，老龄化是发病率、死亡率和卫生保健费用的重要原因，并与糖尿病和动脉粥样硬化有关。有证据证明饮食限制（DR）的抗衰老作用存在于各种实验室动物中。在不同年龄的小鼠、大鼠和非人灵长类动物中，使用各种DR方案，也已明确证明血糖水平长期降低。事实上，有研究表明，降低血糖可能是DR延缓衰老机制的重要组成部分。此外，下丘脑在进食和饮水等过程中发挥的极其重要的作用及其在葡萄糖调节中的密切参与是众所周知的。然而，在体内的特异性和机制，负责降低血糖的抗衰老作用后DR仍然是未知的。我们的总体长期目标是了解DR后血糖降低的下丘脑机制，并根据所获得的知识制定有效的预防和治疗抗衰老策略。这个特定的应用程序的目的是在体内监测葡萄糖代谢的下丘脑与老化和逆转与DR，使用功能性磁共振成像（fMRI）的变化。中心假设是，衰老改变下丘脑的葡萄糖调节和DR延缓这种年龄相关的变化。在我们早期的研究中获得的数据表明，DR在大鼠的一天中和整个生命周期内降低血浆葡萄糖水平。提出的研究的基本原理是，一旦在饮食限制的大鼠中用fMRI获得下丘脑反应的知识，随后可以确定对此负责的机制。我们已经为这个项目做好了充分的准备，因为我们团队的研究已经产生了关于DR对大鼠影响的新观察，并且已经成功地证明了体内下丘脑的fMRI反应（信号强度变化是基础血流量，血容量，以及与潜在神经活动相关的血氧）。将通过追求以下具体目标来检验中心假设并实现本申请的目的：（a）确定大鼠下丘脑中的葡萄糖代谢是否随着衰老而改变以及DR是否逆转它;以及（B）确定这些与年龄相关的变化是否可以在小鼠中检测到，以便能够在将来使用转基因模型。所提出的工作新颖、创新。并且预期证明在由腹膜内葡萄糖给药诱导的正常fMRI下丘脑反应中，随着年龄的增长存在显著的改变。这些结果将对我们理解DR中的葡萄糖调节产生重大影响。此外，它们将在将来研究DR在转基因小鼠模型中的作用方面具有极其重要的价值。最后，这项研究有望为衰老研究做出新的贡献，并有望最终减少与衰老相关的并发症。