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，药理学剂量的 NA 还通过结合并激活 G 蛋白来抑制脂肪细胞中的脂肪分解。质膜中的偶联受体（即 NA 受体） 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。新的概念是，大脑中存在表达 NA-R 的细胞，并且 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新机制。 HPA 轴激活并探索其生理作用最近，b-羟基丁酸 (¿HB) 被证明是 NA-R 的内源性配体； HB 达到的水平会在各种代谢状态下显着刺激 NA-R，这意味着，所有这些代谢状态的特征都是激活的 HPA 轴，但根据我们的研究，其潜在机制在很大程度上是未知的。发现 NA 激活 HPA 轴，我们追查激活的 HPA 轴是由于血浆增加 ¿ HB 可以刺激大脑中的 NA-R 目标 1：测试 NA 通过 NA-R 和前列腺素合成介导的直接作用激活 HPA 轴的假设。由脑室内（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）或我们还将尝试通过检查 NA 输注期间各个大脑区域的 NA-R 表达和神经激活来识别参与 NA 效应的离散大脑区域。等离子体 HB 通过大脑中的 NA-R 作为 HPA 轴的关键刺激物，负责饥饿和糖尿病时 HPA 轴的激活。我们将在大鼠中检查 HPA 轴是否由血浆急性升高激活。 HB 水平以及这种效应是否会被 PTX 或 COX 抑制剂的静脉输注所阻断。我们还将检查饥饿和糖尿病对血浆的影响 ¿野生型和 NA-R 敲除小鼠中的 HB、ACTH 和皮质酮水平，并测试 HPA 轴是否在野生型中被激活，但在 NA-R 敲除小鼠中则没有，尽管血浆有类似的增加 ¿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）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）中激活的 HPA 轴以及降血脂的不良影响提供重要的临床意义。药物不适用。 公共健康相关性：拟议的研究涉及一种涉及降脂药物烟酸的刺激皮质醇分泌的新机制。拟议的研究结果将为某些疾病（例如糖尿病和神经性厌食症）中皮质醇分泌过多提供重要的临床意义。 ）以及烟酸疗法对血脂控制的不良影响。