"A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes"

Abstract

Background: The hormone ghrelin stimulates food intake, promotes adiposity, increases body weight, and elevates blood glucose. Consequently, alterations in plasma ghrelin levels and the functioning of other components of the broader ghrelin system have been proposed as potential contributors to obesity and diabetes. Furthermore, targeting the ghrelin system has been proposed as a novel therapeutic strategy for obesity and diabetes.

Scope of review: The current review focuses on the potential for targeting ghrelin and other proteins comprising the ghrelin system as a treatment for obesity and diabetes. The main components of the ghrelin system are introduced. Data supporting a role for the endogenous ghrelin system in the development of obesity and diabetes along with data that seemingly refute such a role are outlined. An argument for further research into the development of ghrelin system-targeted therapeutic agents is delineated. Also, an evidence-based discussion of potential factors and contexts that might influence the efficacy of this class of therapeutics is provided.

Major conclusions: It would not be a "leap to" conclusions to suggest that agents which target the ghrelin system - including those that lower acyl-ghrelin levels, raise LEAP2 levels, block GHSR activity, and/or raise desacyl-ghrelin signaling - could represent efficacious novel treatments for obesity and diabetes.

Keywords: Diabetes; GHSR; GOAT; Ghrelin; LEAP2; Obesity.

Figure 1

Major components of the ghrelin system and classes of therapeutic agents that could potentially be used to treat obesity and diabetes. The hormone ghrelin acts by binding to its receptor GHSR. To do so, it must first be post-translationally modified by the addition of an acyl-group (most often, an octanoyl group), which is catalyzed by the enzyme GOAT. MRAP2 binds intracellularly to GHSR, and in so doing, facilitates ghrelin's orexigenic actions (and perhaps, others of ghrelin actions) while also inhibiting constitutive (ghrelin-independent) GHSR signaling. The hormone LEAP2 was recently identified as a potent GHSR antagonist (blocking ghrelin action) and inverse agonist (attenuating constitutive GHSR signaling). Compounds shown experimentally to target these different ghrelin system components that could potentially be used as anti-obesity and/or anti-diabetic therapeutic agents include GHSR antagonists, neutralizing anti-ghrelin L-RNA aptamers, cyclized desacyl-ghrelin analogs, GOAT inhibitors, LEAP2, LEAP2-derived analogs, and GHSR inverse agonists.

Figure 2

Factors and contexts that might influence the efficacy of ghrelin system-targeted therapeutic agents in treating obesity and diabetes. While the safety and efficacy of compounds which lower acyl-ghrelin, raise LEAP2, block GHSR activity, and/or raise desacyl-ghrelin signaling remain to be fully tested in clinical trials, studies have provided clues as to clinical scenarios that may heighten their anti-obesity and/or anti-diabetic effects or alternatively might result in negative consequences. These factors and contexts and specific scenarios in which therapeutic agents that block ghrelin/GHSR signaling might be particularly beneficial or detrimental are summarized here and discussed further in the text.

Figure 3

Model illustrating the coordinated response of ghrelin and LEAP2 to obesity and the proposed metabolic effects of a therapeutic intervention that would further raise the plasma LEAP2/ghrelin molar ratio. Top: Obesity is associated with an increase in plasma LEAP2 and a decrease in plasma ghrelin. The resulting increased plasma LEAP2/ghrelin molar ratio serves to limit food intake, body weight, and blood glucose, or rather, processes that would otherwise exacerbate obesity and glucose intolerance. Bottom: Therapeutic interventions that increase plasma LEAP2 and/or decrease plasma ghrelin, such as many of those illustrated in Figure 1, would further increase the plasma LEAP2/ghrelin molar ratio. In turn, food intake, body weight, and blood glucose would be further limited, as would the development of obesity and glucose intolerance in obesogenic environments.