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

HPA 轴激活的新机制：烟酸受体在

• 批准号: 8031153
• 负责人: JANG H. YOUN
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8031153
• 关键词: Acetoacetates; Acetone; Acute; Address; Adipocytes; Agonist; Anorexia Nervosa; Antibodies; Area; Binding; Brain; Brain region; Cell membrane; Cells; Clinical; Corticosterone; Corticotropin; Cyclooxygenase Inhibitors; Data; Diabetes Mellitus; Disease; Dose; Energy-Generating Resources; Food Intake Regulation; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; HM74 gene; Human; Hydrocortisone; Hydroxybutyrates; Indomethacin; Infusion procedures; Intravenous infusion procedures; Investigation; Ketone Bodies; Knockout Mice; Lead; Ligands; Light; Link; Lipids; Lipolysis; Liver; Mediating; Metabolic; Mus; Neurons; Neurosecretory Systems; Nicotinic Acids; Nicotinic Receptors; Peripheral; Pertussis Toxin; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plasma; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Research; Rodent; Role; Staining method; Stains; Starvation; Testing; Tissues; Vitamin B Complex; Vitamins; Water; Water-Soluble Vitamin; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; innovation; lipid metabolism; novel; protein expression; receptor; sensor

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.

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，在药理学剂量下，NA通过结合和激活质膜中的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）也在少数其他组织中表达，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刺激这些细胞产生前列腺素并激活下丘脑-垂体-肾上腺（HPA）轴。本研究的目的是测试下丘脑轴激活的潜在新机制，并探讨其生理作用。最近，b-羟基丁酸酯（¿HB）被证明是NA-R的内源性配体；血浆血红蛋白达到在各种代谢状态（包括饥饿、糖尿病和神经性厌食症）中会显著刺激NA-R的水平。有趣的是，所有这些代谢状态都以HPA轴激活为特征，但其潜在机制在很大程度上是未知的。根据NA激活HPA轴的发现，我们假设HPA轴的激活是由于血浆中增加的HB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脑内直接作用激活HPA轴的假设。我们将在大鼠中研究脑室内（icv）输注各种NA-R激动剂是否激活HPA轴，以及这些作用是否被icv输注百日咳毒素（PTX； g蛋白抑制剂）或环氧化酶（COX；或前列腺素合成酶抑制剂）阻断。我们还将通过检测NA- r表达和NA输注期间神经元激活的不同脑区，试图识别与NA效应相关的离散脑区。目的2：验证血浆血红蛋白通过脑内NA- R作为HPA轴的关键刺激因子，在饥饿和糖尿病中负责HPA轴的激活的假设。我们将在大鼠中研究HPA轴是否因血浆血红蛋白水平的急性升高而被激活，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，并测试野生型小鼠的HPA轴是否被激活，而NA-R敲除小鼠的HPA轴是否被激活，尽管血浆HB水平也有类似的增加。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（如糖尿病和神经性厌食症）中活化的HPA轴和降血脂药物NA的不良影响提供重要的临床意义。