Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor–Knockout Mouse

Background & Aims: The G-protein–coupled receptor GPR39 is a member of a family that includes the receptors for ghrelin and motilin. Recently the peptide obestatin was identified as a natural ligand for GPR39. The objective of this study was to gain insight into the biological function of the GPR39 receptor. Methods: GPR39−/− mice were generated and analyzed. Results: Endogenous GPR39 expression was detected in the brain (septum-amygdala) and the gastrointestinal system (parietal cells, enterocytes, neurons, and pancreas). Gastric emptying of a solid meal (measured by the 14C octanoic breath test) in GPR39−/− mice was accelerated significantly with a gastric half-emptying time of 49.5 ± 2.2 minutes compared with 86.9 ± 8.4 minutes in GPR39+/+ mice. A more effective expulsion of distally located pellets (30%–75% of length) was observed in the colon of GPR39−/− mice. Four hours after pylorus ligation, the volume of gastric secretion was increased significantly (GPR39−/−: 638 ± 336 μL; GPR39+/+: 225 ± 170 μL), but gastric acid secretion was unchanged. The mature body weight and body fat composition of GPR39−/− mice was significantly higher compared with GPR39+/+ mice, but this was not related to hyperphagia because 24-hour food intake did not differ between both genotypes. In contrast, deficiency of the GPR39 receptor led to reduced hyperphagia after fasting. The cholesterol levels were increased significantly in the GPR39−/− mice. Conclusions: Our data partially confirm and extend the described in vivo effects of obestatin and suggest that this peptide plays a functional role in the regulation of gastrointestinal and metabolic function through interaction with the GPR39 receptor.