Control of ketogenesis by epinephrine and GPR109A

肾上腺素和 GPR109A 控制生酮

基本信息

批准号：
9037005
负责人：
MATTHEW WHIM
金额：
$ 32.49万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037005
关键词：
Acute Adipocytes Adrenal Glands Adrenal Medulla Agonist Blood Brain Catecholamines Child Chromaffin Cells Cyclic AMP-Dependent Protein Kinases Diabetic Ketoacidosis Electrophysiology (science)Energy-Generating Resources Ensure Enzymes Epinephrine Failure Fasting Fatty Acids Feedback Food deprivation (experimental)G-Protein-Coupled Receptors Glucose Health Hormones Hydroxybutyrates In Situ Insulin Insulin-Dependent Diabetes Mellitus Ketone Bodies Ketones Lead Life Lipolysis Liver Mammals Mediating Metabolic Metabolic Diseases Modeling Monitor Mus Nervous system structure Onset of illness Organ Orphan Output Pathway interactions Physiological Plasma Process Production Receptor Activation Regulation Risk Signal Pathway Signal Transduction Sympathetic Nervous System System Technology Testing Time Tissues Transgenic Organisms Tyrosine 3-Monooxygenase Tyrosine Hydroxylase Inhibitor designer receptors exclusively activated by designer drugs in vivo ketogenesis ketogentic neuropeptide Y novel novel strategies prevent receptor research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Ketone bodies are energy-rich molecules which circulate in the blood. They are essential during the response to fasting when their levels in the blood rise. During this time they provide an alternative energy source which is used by many tissues and ensures that the nervous system, which preferentially uses glucose, can remain adequately supplied. Normally the plasma level of ketone bodies is tightly regulated. However under some circumstances, such as poorly managed type I diabetes, their levels rise and this can lead to ketoacidosis, a potentially life-threatening condition. The long-term objective of the proposed study is to determine the mechanisms that control ketogenesis. The primary hormone that stimulates ketone body production is epinephrine which is released from chromaffin cells in the adrenal medulla, a branch of the sympathetic nervous system. During fasting the secretion of epinephrine is increased and this leads to elevated lipolysis and consequent ketogenesis. A major puzzle is the mechanism that restrains ketogenesis once it is initiated. What normally prevents a pathological rise in ketone bodies in these circumstances? Our hypothesis is that a recently identified G protein-coupled receptor termed GPR109A is a key component of a negative feedback loop that regulates ketogenesis by inhibiting epinephrine release. The endogenous agonist of GPR109A is Beta-OHB, the most abundant ketone body. To test this idea we have two specific aims. In the first set of experiments we will test the idea that GPR109A receptors are expressed by chromaffin cells and that during fasting these receptors are activated by the increased levels of Beta OHB in the blood. As a result, the secretion of epinephrine is acutely inhibited and the ketogenic drive is reduced. Our second specific aim is to test the hypothesis that the activation of GPR109A receptors during ketogenesis leads to a long-lasting suppression of epinephrine synthesis and that this effect is mediated by a local adrenal signaling loop that inhibits the expression of tyrosine hydroxylase, the rate limiting step for catecholamine synthesis. Using in situ and in vivo approaches to monitor epinephrine release and the levels of ketone bodies, we aim to determine how ketogenesis is regulated under physiological conditions and ultimately whether this control system is altered in metabolic disease.

描述（由申请人提供）：酮体是富含能量的分子，它们在血液中循环。当它们在血液中的水平上升时，它们在对禁食的反应中至关重要。在此期间，它们提供了许多组织使用的替代能源，并确保优先使用葡萄糖的神经系统可以保持充分的供应。通常，酮体的血浆水平受到严格调节。但是，在某些情况下，例如管理不良的I型糖尿病，它们的水平升高，这可能导致酮症酸中毒，这可能是一种潜在的威胁生命的疾病。拟议的研究的长期目标是确定控制酮作用的机制。刺激酮体产生的主要激素是肾上腺素，它是从肾上腺髓质细胞中释放的，肾上腺髓质细胞是交感神经系统的一个分支。在禁食过程中，肾上腺素的分泌增加，这导致脂解升高并随之而来的生酮发生。一个主要的难题是一旦启动生酮的机制，它就会限制它。在这种情况下，通常阻止酮体病理升高的原因是什么？我们的假设是，最近鉴定出的称为GPR109A的G蛋白偶联受体是负反馈回路的关键组成部分，该循环通过抑制肾上腺素释放来调节酮的发生。 GPR109A的内源性激动剂是β-OHB，是最丰富的酮体。为了测试这个想法，我们有两个具体的目标。在第一组实验中，我们将测试GPR109A受体由铬蛋白细胞表达的想法，并且在禁食期间，这些受体会因血液中βOHB水平的升高而激活。结果，肾上腺素的分泌被急性抑制，生酮驱动降低。我们的第二个具体目的是检验以下假设：生酮发生过程中GPR109a受体的激活导致肾上腺素合成的长期抑制，并且这种作用是由局部肾上腺信号传导循环介导的，该肾上腺肾上腺信号循环抑制了酪氨酸羟化酶的表达步用于儿茶酚胺合成。使用原位和体内方法来监测肾上腺素释放和酮体的水平，我们旨在确定如何在生理条件下调节生酮的发生，并最终在代谢疾病中改变这种控制系统。