The metabolic effects of ghrelin on muscle, adipose and liver.

背景资料。Ghrelin是一种胃肽，以其促食欲(刺激食欲)作用而闻名。血浆Ghrelin浓度在进餐前急剧升高，在进食后下降。Ghrelin以两种亚型存在，即酰化(AG)和脱酰化(DAG)Ghrelin。虽然DAG最近被证明对周围组织有代谢作用，但AG被认为是促食欲素作用的生物活性形式。AG是生长激素促分泌素受体1a亚型(GHS-R1a)的配体，启动生长激素(GH)的释放。许多研究表明，Ghrelin输注会损害葡萄糖从血液中的清除；然而，这些研究使用的剂量范围很大，通常是非生理性的，无法区分Ghrelin的直接影响和GH继发性增加所致的影响。Ghrelin被认为是长期禁食期间防止极端低血糖的重要机制的一部分，它通过刺激GH释放，从而促进脂解和血糖的保存。令人惊讶的是，AG和DAG对胰岛素敏感组织、骨骼肌、脂肪和肝脏的直接代谢影响还没有得到彻底的研究，而不是GH的影响。血浆Ghrelin浓度在习惯性用餐前最高。由于Ghrelin最公认的作用是刺激食物摄取，令人惊讶的是，人们几乎忽略了Ghrelin对胰岛素敏感组织是否具有快速、剧烈的影响，作为对一顿饭的“准备反应”的一部分。我们的论点是，在进食前胃促生长素的升高有助于胰岛素敏感的组织为摄入的营养物质的输送做准备。据我们所知，Ghrelin的这种潜在作用还没有被研究过。这项拨款提案的总体目标是确定Ghrelin的两种主要异构体(AG和DAG)对肌肉、脂肪组织和肝脏中葡萄糖和脂肪酸(FA)代谢的快速、直接影响，而不是GH的影响。具体地说，我们的假设是Ghrelin能显著增强胰岛素的能力：i)刺激肌肉和脂肪组织中葡萄糖和FA的摄取；ii)促进葡萄糖和FA在肌肉中的储存；iii)抑制脂肪组织和肌肉中的脂肪分解，以及iv)抑制肝脏葡萄糖的产生。相反，我们假设Ghrelin不是独立的，即在没有胰岛素的情况下，刺激葡萄糖和FA的摄取和储存，或抑制脂解或肝脏葡萄糖的产生。在缺乏营养摄入的情况下，这种影响可能会导致血糖的灾难性下降。这些研究的发现可能揭示了Ghrelin以前未被认识到的生理作用。

Background. Ghrelin is a gastric peptide best known for its orexigenic (appetite-stimulating) effects. Plasma ghrelin concentrations rise sharply prior to entrained mealtimes and decline following the consumption of food. Ghrelin exists as two isoforms, acylated (AG) and deacylated (DAG) ghrelin. AG is considered the bioactive form in terms of orexigenic actions, although DAG has recently been demonstrated to have metabolic effects on peripheral tissues. AG is a ligand for the growth hormone secretagogue receptor subtype 1a (GHS-R1a) and initiates growth hormone (GH) release. A number of studies suggest that ghrelin infusion impairs the clearance of glucose from the blood; however, these studies utilize a wide range of dosages which are often nonphysiological, and are unable to distinguish between the direct effects of ghrelin vs. those due to the secondary increase in GH. It has been postulated that ghrelin is part of an important mechanism to prevent extreme hypoglycemia during a prolonged fast by stimulating GH release and thereby facilitating lipolysis and the preservation of blood glucose. Surprisingly, the direct metabolic effects of AG and DAG on insulin sensitive tissues, skeletal muscle, adipose and liver, independent of the effects of GH have not been thoroughly examined.******Rationale of Proposed Studies. Plasma ghrelin concentration is highest immediately before habitual mealtime. Since the best recognized effect of ghrelin is to stimulate food intake, it is surprising that it has been virtually ignored whether ghrelin has a rapid, acute effect on insulin sensitive tissues as part of a "preparatory response" to a meal. It is our contention that the rise in ghrelin just prior to the consumption of food serves to prime insulin sensitive tissues in preparation for the delivery of ingested nutrients. To our knowledge, this potential role of ghrelin has not been examined. The overall aim of this grant proposal is to determine the rapid, direct effects of ghrelin's two main isoforms (AG, DAG) on glucose and fatty acid (FA) metabolism in muscle, adipose tissue and liver, independent of the effects of GH. Specifically, it is our hypothesis that ghrelin acutely enhances the ability of insulin to i) stimulate glucose and FA uptake in muscle and adipose tissue; ii) facilitate the storage of glucose and FAs in muscle; iii) inhibit lipolysis in adipose tissue and muscle, and iv) inhibit hepatic glucose production. Conversely, we hypothesize that ghrelin will NOT independently i.e. in the absence of insulin, stimulate glucose and FA uptake and storage, or inhibit lipolysis or hepatic glucose production. Such effects in the absence of nutrient ingestion would potentially lead to a catastrophic decline in blood glucose. The findings of these studies may reveal a previously unrecognized physiological role of ghrelin.**