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

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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.