Control of ketogenesis by epinephrine and GPR109A

描述（申请人提供）：酮体是富含能量的分子，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是必不可少的。在此期间，它们提供了一种可供许多组织使用的替代能量来源，并确保优先使用葡萄糖的神经系统能够保持充足的供应。正常情况下，血浆中酮体水平受到严格调节。然而，在某些情况下，例如管理不善的I型糖尿病，它们的水平会上升，这可能导致酮症酸中毒，这是一种潜在的危及生命的疾病。这项研究的长期目标是确定控制生酮的机制。刺激酮体产生的主要激素是肾上腺素，肾上腺素是从肾上腺髓质（交感神经系统的一个分支）中的嗜铬细胞释放出来的。在禁食期间，肾上腺素的分泌增加，这导致脂肪分解和随之而来的酮生成。一个主要的谜团是，一旦生酮开始，抑制生酮的机制。在这种情况下，通常是什么阻止了酮体的病理增加？我们的假设是，最近发现的一种名为GPR109A的G蛋白偶联受体是通过抑制肾上腺素释放来调节酮生成的负反馈回路的关键组成部分。GPR109A的内源性激动剂是β - ohb，这是最丰富的酮体。为了验证这个想法，我们有两个具体的目标。在第一组实验中，我们将测试GPR109A受体是由嗜铬细胞表达的，并且在禁食期间，这些受体被血液中β OHB水平的增加所激活。结果，肾上腺素的分泌被严重抑制，生酮驱动被降低。我们的第二个具体目标是验证以下假设：在生酮过程中，GPR109A受体的激活导致肾上腺素合成的长期抑制，这种作用是由局部肾上腺信号环介导的，该信号环抑制酪氨酸羟化酶的表达，这是限速步骤

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.