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

描述（由申请人提供）：烟酸（NA;或烟酸）是一种水溶性维生素。除了其作为维生素的功能之外，药理学剂量的NA通过结合并激活G蛋白偶联受体（即，NA受体）。NA受体（NA-R）也在一些其他组织中表达，但其在非脂肪组织中的功能尚不清楚。我们的初步数据提出了新的概念，即大脑中有表达NA-R的细胞，NA刺激这些细胞产生肾上腺素并激活下丘脑-垂体-肾上腺（HPA）轴。本提案的目的是测试HPA轴激活的这种潜在的新机制，并探索其生理作用。最近，研究表明b-羟基丁酸酯（â HB）是NA-R的内源性配体;血浆â HB达到的水平在各种代谢状态下（包括饥饿、糖尿病和神经性厌食症）会大幅刺激NA-R。有趣的是，所有这些代谢状态的特征是激活HPA轴，但其潜在的机制在很大程度上是未知的。根据我们的发现，NA激活HPA轴，我们假设激活HPA轴是由于血浆HB的增加，可以刺激大脑中的NA-R。目的1：验证NA通过NA-R和前列腺素合成介导的大脑直接作用激活HPA轴的假设。我们将在大鼠中检查脑室内（icv）输注各种NA-R激动剂是否激活HPA轴，以及icv输注百日咳毒素（PTX; G蛋白抑制剂）或环氧合酶（考克斯;或前列腺素合酶）抑制剂是否阻断这些作用。我们还将尝试通过检查NA输注过程中NA-R表达和神经元激活的各个脑区来确定NA效应所涉及的离散脑区。目标二：检验血浆HB通过大脑中的NA-R作为HPA轴的关键刺激物发挥作用，并负责饥饿和糖尿病中HPA轴的激活的假设。我们将在大鼠中检查HPA轴是否被血浆HB水平的急性升高激活，以及这种作用是否被PTX或COX抑制剂的icv输注阻断。我们还将研究饥饿和糖尿病对野生型和NA-R敲除小鼠血浆<$HB、ACTH和皮质酮水平的影响，并测试HPA轴是否在野生型中被激活，但在NA-R敲除小鼠中没有激活，尽管血浆<$HB水平也有类似的增加。因此，在本项目中，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，以及外周脂质代谢（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（例如，糖尿病和神经性厌食症）和降血脂药物NA的不良影响。 公共卫生相关性：这项研究提出了一种新的机制，刺激皮质醇分泌涉及降脂药物烟酸。拟议的研究结果将为某些疾病中皮质醇分泌过多提供重要的临床意义（例如，糖尿病和神经性厌食症）和用于血脂控制的烟酸疗法的不良影响。

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.