A Novel Mechanism of HPA Axis Activation: Role of Nicotinic Acid Receptor in the

说明(申请人提供)：烟酸(NA；或烟酸)是一种水溶性维生素。除了作为维生素的功能，NA在药物剂量下，通过与质膜上的G蛋白偶联受体(即NA受体)结合并激活来抑制脂肪细胞的脂解。NA受体(NA-R)在其他一些组织中也有表达，但其在非脂肪组织中的功能尚不清楚。我们的初步数据提示了一个新的概念，即大脑中有表达NA-R的细胞，NA刺激这些细胞产生前列腺素并激活下丘脑-垂体-肾上腺轴(HPA)。这项建议的目的是测试这一潜在的新的HPA轴激活机制，并探索其生理作用。最近，b-羟基丁酸酯(？HB)被证明是NA-R的内源性配体；血浆？Hb达到的水平可以在各种代谢状态下显著刺激NA-R，包括饥饿、糖尿病和神经性厌食症。有趣的是，所有这些代谢状态都以激活的HPA轴为特征，但其潜在的机制在很大程度上尚不清楚。根据我们的发现，NA激活了HPA轴，我们假设HPA轴的激活是由于血浆Hb的增加，这可能会刺激大脑中的NA-R。目的1：验证NA通过NA-R和前列腺素合成在大脑中的直接作用激活HPA轴的假说。我们将检查大鼠的HPA轴是否被脑室内注射各种NA-R激动剂激活，以及这些作用是否被脑室注射百日咳毒素(PTX；G蛋白抑制剂)或环氧合酶(COX；或前列腺素合成酶)抑制剂所阻断。我们还将尝试通过检测NA输注过程中NA-R表达和神经元激活的不同脑区，来确定与NA效应有关的离散脑区。目的2：验证如下假设：血浆Hb通过脑内NA-R作为HPA轴的关键刺激因子，在饥饿和糖尿病中参与HPA轴的激活。我们将在大鼠身上检测HPA轴是否被血浆Hb水平的急性升高所激活，以及这种作用是否被脑室注射PTX或COX抑制剂所阻断。我们还将检查饥饿和糖尿病对野生型和NA-R基因敲除小鼠血浆Hb、ACTH和皮质酮水平的影响，并测试HPA轴在野生型和NA-R基因敲除小鼠中是否被激活，但在NA-R基因敲除小鼠中不被激活，尽管血浆Hb水平有类似的增加。因此，在这个项目中，我们将测试高度创新的概念，即NA通过大脑中的NA-R激活HPA轴，以及外周脂肪代谢(或HB)和神经内分泌功能(HPA轴)之间存在联系。如果这些概念被证明是正确的，它将开辟许多新的研究领域，并为某些疾病(如糖尿病和神经性厌食症)和降血脂药物NA的不良影响的激活的HPA轴提供重要的临床意义。 与公共健康相关：这项拟议的研究提出了一种新的刺激皮质醇分泌的机制，涉及降脂药物烟酸。拟议的研究结果将为某些疾病(如糖尿病和神经性厌食症)的皮质醇分泌过多以及烟酸疗法控制血脂的不良影响提供重要的临床意义。

DESCRIPTION (provided by applicant): Nicotinic acid (NA; or niacin) is a water-soluble vitamin. In addition to its function as a vitamin, NA, at pharmacological doses, inhibits lipolysis in adipocytes by binding to and activating a G-protein coupled receptor (i.e., NA receptor) in the plasma membrane. The NA receptor (NA-R) is also expressed in a few other tissues, but its functions in non-adipose tissues are unclear. Our preliminary data suggest the novel concepts that there are cells in the brain that express NA-R, and NA stimulates these cells to produce prostaglandins and activate the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this proposal are to test for this potentially novel mechanism for HPA axis activation and to explore its physiological roles. Recently, b-hydroxybutyrate (¿HB) was shown to be an endogenous ligand for NA-R; plasma ¿HB reaches levels that would substantially stimulate NA-R in various metabolic states, including starvation, diabetes, and anorexia nervosa. Interestingly, all of these metabolic states are characterized by activated HPA axis, but the underlying mechanisms are largely unknown. In light of our finding that NA activates the HPA axis, we hypothesize that the activated HPA axis is due to increased plasma ¿HB that could stimulate NA-R in the brain. Aim 1: Test the hypothesis that NA activates the HPA axis by direct actions in the brain that are mediated through NA-R and prostaglandin synthesis. We will examine in rats whether the HPA axis is activated by intracerebroventricular (icv) infusions of various NA-R agonists, and whether these effects are blocked by an icv infusion of pertussis toxin (PTX; G-protein inhibitor) or cyclooxygenase (COX; or prostaglandin synthase) inhibitors. We will also attempt to identify discrete brain regions involved in the NA effect by examining various brain regions for the expression of NA-R and neuronal activation during NA infusion. Aim 2: Test the hypothesis that plasma ¿HB functions as a key stimulator of the HPA axis via NA- R in the brain and is responsible for HPA axis activation in starvation and diabetes. We will examine in rats whether the HPA axis is activated by an acute elevation of plasma ¿HB level and whether this effect is blocked by an icv infusion of PTX or COX inhibitors. We will also examine the effects of starvation and diabetes on plasma ¿HB, ACTH, and corticosterone levels in wild-type and NA-R knockout mice and test whether the HPA axis is activated in wild-type, but not in NA-R knockout mice despite similar increases in plasma ¿HB levels. Thus, in this project we will test the highly innovated concepts that NA activates the HPA axis via NA-R in the brain and that there is a link between peripheral lipid metabolism (or ¿HB) and neuroendocrine functions (HPA axis). If these concepts are proven true, it would open up many new areas of investigation and provide important clinical implications for activated HPA axis in certain diseases (e.g., diabetes and anorexia nervosa) and unwanted effects of the hypolipidemic drug NA. PUBLIC HEALTH RELEVANCE: The proposed research addresses a novel mechanism for stimulation of cortisol secretion involving the lipid-lowering drug nicotinic acid. The result of the proposed research would provide important clinical implications for excessive cortisol secretion in certain diseases (e.g., diabetes and anorexia nervosa) and unwanted effects of the nicotinic acid therapy for lipid control.