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

背景 Ghrelin是一种胃肽，以其促食欲（刺激食欲）作用而闻名。血浆ghrelin浓度急剧上升前夹带进餐时间和下降后的消费的食物。生长素释放肽有两种亚型，酰化（AG）和脱酰化（DAG）生长素释放肽。AG被认为是食欲活动方面的生物活性形式，尽管DAG最近已被证明对外周组织具有代谢作用。AG是生长激素促分泌素受体亚型1a（GHS-R1 a）的配体，并启动生长激素（GH）释放。许多研究表明，生长激素释放肽输注会损害葡萄糖从血液中的清除;然而，这些研究使用了广泛的剂量，这些剂量通常是非生理性的，并且无法区分生长激素释放肽的直接作用与继发性生长激素增加的作用。据推测，生长激素释放肽是通过刺激GH释放从而促进脂解和血糖保存来防止长时间禁食期间极端低血糖的重要机制的一部分。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作用与GH的作用无关，尚未得到彻底的研究。 拟定研究的依据。 血浆ghrelin浓度在习惯性进餐时间之前最高。 由于生长素释放肽的最佳公认作用是刺激食物摄入，令人惊讶的是，生长素释放肽是否对胰岛素敏感组织具有快速、急性作用作为对膳食的“预备反应”的一部分几乎被忽视。我们的论点是，在食物消耗之前胃饥饿素的升高用于准备胰岛素敏感组织，以准备输送摄入的营养素。据我们所知，ghrelin的这种潜在作用尚未得到研究。 这项拨款提案的总体目标是确定生长激素释放肽的两种主要亚型（AG，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，独立于GH的影响。具体而言，我们的假设是，生长素释放肽急性增强胰岛素i）刺激肌肉和脂肪组织中的葡萄糖和FA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解，以及iv）抑制肝葡萄糖产生的能力。相反，我们假设生长激素释放肽不会独立地，即在没有胰岛素的情况下，刺激葡萄糖和脂肪酸的摄取和储存，或抑制脂解或肝葡萄糖的产生。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。这些研究的结果可能揭示了以前未被认识到的ghrelin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.