Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure

Background & Aims: Gut-derived peptides including ghrelin, cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide (GLP-1), and GLP-2 exert overlapping actions on energy homeostasis through defined G-protein-coupled receptors (GPCRs). The proglucagon-derived peptide (PGDP) oxyntomodulin (OXM) is cosecreted with GLP-1 and inhibits feeding in rodents and humans; however, a distinct receptor for OXM has not been identified. Methods: We examined the mechanisms mediating oxyntomodulin action using stable cell lines expressing specific PGDP receptors in vitro and both wild- type and knockout mice in vivo. Results: OXM activates signaling pathways in cells through glucagon or GLP-1 receptors (GLP-IR) but transiently inhibits food intake in vivo exclusively through the GLP-IR. Both OXM and the GLP-IR agonist exendin-4 (Ex-4) activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract following intraperitoneal (IP) injection. However, OXM transiently inhibited food intake in wild-type mice following intracerebroventricular (ICV) but not IP administration, whereas Ex-4 produced a more potent and sustained inhibition of food intake following both lCV and IP administration. The anorectic effects of OXM were preserved in Gcgr(-/-) mice but abolished in GLP-1R(-/-) mice. Although central Ex-4 and OXM inhibited feeding via a GLP-1R-dependent mechanism, Ex-4 but not OXM reduced VO2 and respiratory quotient in wild-type mice. Conclusions: These findings demonstrate that structurally distinct PGDPs differentially regulate food intake and energy expenditure by interacting with a GLP-1R-dependent pathway. Hence ligand-specific activation of a common GILP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure.