HYPOTHALAMIC DYSFUNCTION AND AGED-RELATED METABOLIC DECLINE

描述(由申请人提供)：营养素可获得性的慢性增加可能有助于衰老的几个关键新陈代谢特征。后者包括(但不限于)腹部脂肪沉积增加(内脏肥胖症)、甘油三酯组织水平增加、胰岛素抵抗、能量消耗相对减少以及动脉粥样硬化疾病(ASCVD)和2型糖尿病(DM2)风险增加。在正常情况下，营养过剩的有害影响会被营养“反调节”系统的迅速激活所抵消。后者包括(但不限于)部分受瘦素控制的下丘脑神经回路。这些营养“逆向调节”系统的激活应该可以防止能量的过度储存和胰岛素抵抗的发生。因此，似乎有一个功能反馈回路，它通常可以防止内脏肥胖、胰岛素抵抗和其他衰老的代谢特征的发展。然而，越来越多的证据表明，衰老是瘦素抵抗的一种状态。与这些最近的发现相一致，这个反馈回路的运行很可能 因此，瘦素可能无法补偿衰老过程中营养过剩的有害影响。因此，我们的建议将重点放在下丘脑对营养过剩的反应机制以及它们在衰老过程中如何改变。我们还希望辨别下丘脑神经回路的损害，这是由于营养供应的慢性增加，而不是由于衰老过程本身。基于初步结果和这一总体假设，我们希望追求以下具体目标：衰老是否改变了瘦素对能量、糖脂代谢和胰岛素的作用？我们将研究瘦素中枢释放与生物学结果之间的剂量-反应关系。我们将特别关注小剂量脑室注射瘦素对代谢终点的影响，而不是行为终点。黑素皮质素途径的刺激能克服衰老的瘦素抵抗吗？我们将验证这一假设，即激活中枢黑素皮质素受体绕过了衰老大鼠瘦素信号的缺陷。

DESCRIPTION (provided by applicant): Chronic increases in the availability of nutrients are likely to contribute to several key metabolic features of aging. The latter include (but are not limited to) increased deposition of fat within the abdominal cavity (visceral adiposity), increased tissue levels of triglycerides, insulin resistance, relative decrease in energy expenditure, and augmented risks for atherosclerotic disease (ASCVD) and for type 2 diabetes mellitus (DM2). Under normal circumstances, the deleterious effects of the excessive availability of nutrients are countered by the prompt activation of nutrient "counter regulatory" systems. The latter include (but are not limited to) hypothalamic neuro-circuitries partly under the control of leptin. The activation of these nutrient "counter regulatory" systems should prevent the excessive storage of energy and the onset of insulin resistance. Thus, there appears to be a functional feedback loop, which normally prevents visceral adiposity, insulin resistance, and other metabolic features of aging from developing. However, there is mounting evidence that aging is a state of leptin resistance. Consistent with these recent findings, the operation of this feedback loop is likely to be impaired and leptin may therefore fail to compensate for the deleterious effects of nutrient excess during the aging process. Our proposal will therefore focus on mechanisms responsible for hypothalamic responses to nutrient excess and how they are altered during aging. We also wish to discern impairments in hypothalamic neuro-circuitries, which are due to chronic increases in nutrient availability from those due to the aging process per se. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: Does aging modify the actions of leptin on energy, glucose and lipid metabolism and on insulin action? We will examine the dose-response relationship between central delivery of leptin and biological outcomes. We will particularly focus on the effect of low dose ICV leptin administration on metabolic rather than behavioral end points. Can stimulation of the melanocortin pathway overcome the leptin resistance of aging? We will test the hypothesis that activation of CNS melanocortin receptors bypasses the defect in leptin signaling in aging rats.