Differential Regulation of Plasma Obestatin and Ghrelin by Meal Intake and the Cholinergic System in Lean, But Not Obese Individuals

Abstract

Context: Obestatin is cosecreted with and stemming from the same precursor as ghrelin and is apparently involved in energy metabolism. Relatively little is known about the regulation of obestatin release. Objective: The regulation of obestatin release and obestatin-to-ghrelin ratios by meal intake and the cholinergic system were studied in lean and obese subjects. Design, Participants, and Setting: We conducted a randomized, double-blind, placebo-controlled, crossover study with 4 study days in eight obese (body mass index Ͼ30 kg/m 2 ) and eight matched lean (body mass index Ͻ25 kg/m 2 ) healthy subjects (two males and six females per group) at a University Clinical Research Unit. Interventions: Atropine (1 mg iv) was administered alone and in combination with breakfast (550 kcal) intake, or placebo (isotonic saline) alone and in combination with breakfast. Main Outcome Measures: We measured plasma obestatin and obestatin/ghrelin ratios. Results: Both obestatin and ghrelin/obestatin ratios decreased significantly from baseline by either atropine or meal intake in lean individuals, with the two effects adding up on the combined atropine/breakfast day. In contrast, there were no statistically significant differences in obese subjects, who also showed significantly greater association between ghrelin and obestatin values than their lean counterparts. Conclusions: Obestatin and ghrelin release is differentially regulated by meal intake and the cholinergic system in lean individuals. This regulation is impaired in obesity. (J Clin Endocrinol Metab 95: 0000 -0000, 2010) G hrelin, the octanoylated peptide produced mainly by the stomach and natural ligand to the GH secretagogue-receptor, is now well established as an orexigenic hormone mediating increased food intake resulting in a positive energy balance (1). Obestatin, an amidated cleavage product of the preproghrelin gene, was initially described as opposing the functions of ghrelin on appetite, resulting in decreased gastric food intake and weight gain in rodents, by binding to its cognate receptor, an (until then) orphan receptor termed g protein coupled receptor 39 (2). These results have been partially confirmed, but also called into question (see Ref. 3 and the references therein). Obestatin does bind to membranes of pancreatic cells and cell lines with high affinity and promotes survival o