title: The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin.
abstract: Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism. Because glucagon decreases food intake in rodents and humans, we examined whether activation of the GCGR is involved in the body weight-lowering effects of OXM. We identified an equipotent GLP1R-selective peptide agonist that differs from OXM by only one residue (Q3→E, OXMQ3E), but has no significant GCGR agonist activity in vitro and ~100-fold reduced ability to stimulate liver glycogenolysis. Chronic treatment of obese mice with OXM and OXMQ3E demonstrated that OXM exhibits superior weight loss and lipid-lowering efficacy, and antihyperglycemic activity that is comparable to the corresponding GLP1R-selective agonist. Studies in Glp1r(-/-) mice and coadministration of OXM and a GCGR antagonist revealed that the antiobesity effect of OXM requires activation of both GLP1R and GCGR. Our data provide new insight into the mechanism of action of OXM and suggest that activation of GCGR is involved in the body weight-lowering action of OXM.
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Kosinski
authors.forename: James
authors.initials: J
authors.lastname: Hubert
authors.forename: Paul E
authors.initials: PE
authors.lastname: Carrington
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: James
authors.initials: J
authors.lastname: Mu
authors.forename: Corey
authors.initials: C
authors.lastname: Miller
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinharoy
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D002149:Energy Intake / Q000187:drug effects / Q000502:physiology*; D005934:Glucagon / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D050261:Glycogenolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D053772:Oxyntomodulin / Q000378:metabolism* / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D005934:Glucagon