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

描述（由申请人提供）：烟酸（NA；或烟酸）是一种水溶性维生素。除了作为维生素的功能外，药理学剂量的 NA 还可以通过结合并激活质膜中的 G 蛋白偶联受体（即 NA 受体）来抑制脂肪细胞中的脂肪分解。 NA 受体（NA-R）也在其他一些组织中表达，但其在非脂肪组织中的功能尚不清楚。我们的初步数据表明，大脑中存在表达 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 (HPA) 轴。该提案的目的是测试这种潜在的 HPA 轴激活新机制并探索其生理作用。最近，b-羟基丁酸（¿HB）被证明是 NA-R 的内源配体；血浆 ¿HB 达到的水平会在各种代谢状态下显着刺激 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，但其潜在机制在很大程度上尚不清楚。根据我们发现 NA 激活 HPA 轴，我们假设激活的 HPA 轴是由于血浆 ¿HB 增加，从而刺激大脑中的 NA-R。目标 1：检验 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 HPA 轴是否被脑室内（icv）输注各种 NA-R 激动剂激活，以及这些作用是否被脑室内输注百日咳毒素（PTX；G 蛋白抑制剂）或环氧合酶（COX；或前列腺素合酶）抑制剂所阻断。我们还将尝试通过检查不同大脑区域的 NA-R 表达和 NA 输注过程中的神经元激活来识别参与 NA 效应的离散大脑区域。目标 2：检验以下假设：血浆 ¿HB 通过大脑中的 NA-R 作为 HPA 轴的关键刺激物，并负责饥饿和糖尿病时 HPA 轴的激活。我们将在大鼠中检查 HPA 轴是否因血浆 HB 水平的急剧升高而被激活，以及这种作用是否被静脉输注 PTX 或 COX 抑制剂所阻断。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，而在 NA-R 敲除小鼠中则不然，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，以及外周脂质代谢（或 ¿HB）与神经内分泌功能（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）中激活的 HPA 轴以及降血脂药物 NA 的不良反应提供重要的临床意义。 公共健康相关性：拟议的研究涉及一种刺激皮质醇分泌的新机制，涉及降脂药物烟酸。拟议研究的结果将为某些疾病（例如糖尿病和神经性厌食症）中皮质醇分泌过多以及烟酸疗法对血脂控制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.