Central Mediation of Growth Hormone Effects in Humans

PROJECT SUMMARY GH and IGF-1 are well known to act on peripheral tissues to importantly influence growth, metabolism and body composition. Recently, however, our preliminary work and other data in mice have suggested that central effects of GH on the orexigenic hypothalamic neuropeptide AgRP (agouti-related protein) may be another important mechanism by which GH exerts its nutritional and metabolic effects. AgRP neurons express GH receptors and in mice, GH was shown to activate AgRP neurons to produce orexigenic responses. The current project stems from our studies in acromegaly, a human model that provides unique insights into the mechanisms of GH/IGF-1 effects. We found novel evidence that plasma levels of AgRP, a marker of hypothalamic AgRP, are higher in active acromegaly than in matched healthy subjects and are lower after surgery that reduced GH/IGF-1 or the GH receptor antagonist pegvisomant that lowered IGF-1 levels. These data suggest that GH excess increases AgRP in humans, but whether GH stimulates AgRP is unknown. Therefore, our 1st objective is to directly test the hypothesis that GH stimulates AgRP in humans. To further investigate the AgRP-GH axis, the effect of the GLP- 1R agonist liraglutide on plasma AgRP levels will also be tested in this project. Peripherally administered liraglutide targets hypothalamic GLP-1Rs and inhibits AgRP neurons in mice. Our 2nd Aim is to show that liraglutide lowers plasma AgRP levels in humans. This effect of liraglutide has not been studied in humans; thus, this study could uncover a key mechanism by which liraglutide affects body weight and metabolism. This project also explores the potential link of GH-stimulated changes in AgRP to GH-induced insulin resistance. AgRP impacts glucose metabolism in mice and plasma AgRP levels in healthy humans reflect differences in insulin resistance. In mice, in the fed state, AgRP overexpression or its’ central infusion impair glucose metabolism. Insulin resistance is a prominent feature of GH excess and GH administration is well known to induce insulin resistance early after its initiation: AgRP rise may contribute to this. By a distinct mechanism of its action, liraglutide, given along with GH, may lower AgRP and thus attenuate the insulin resistance that occurs with GH alone. Liraglutide has not been tested for treatment of the clinically important problem of GH-induced insulin resistance and thus novel, important data in this regard will be generated. We will test these hypotheses in a randomized, placebo-controlled study in which we will administer supraphysiologic and replacement GH to healthy and GH deficient humans, respectively, with and without co-administration of liraglutide. This project utilizes human models to investigate the GH-AgRP axis, potentially a key mechanism of GH action and mediator of GH-induced insulin resistance, and will provide valuable insights into the roles of AgRP and the GH-AgRP axis in human disorders of GH, nutrition and growth.