title: Pharmacological targeting of glucagon and glucagon-like peptide 1 receptors has different effects on energy state and glucose homeostasis in diet-induced obese mice.
abstract: Pharmacologic contributions of directly agonizing glucagon-like peptide 1 (GLP-1) receptor or antagonizing glucagon receptor (GCGR) on energy state and glucose homeostasis were assessed in diet-induced obese (DIO) mice. Metabolic rate and respiratory quotient (RQ), hyperglycemic clamp, stable isotope-based dynamic metabolic profiling (SiDMAP) studies of (13)C-labeled glucose during glucose tolerance test (GTT) and gene expression were assessed in cohorts of DIO mice after a single administration of GLP-1 analog [GLP-1-(23)] or anti-GCGR antibody (Ab). GLP-1-(23) and GCGR Ab similarly improved GTT. GLP-1-(23) decreased food intake and body weight trended lower. GCGR Ab modestly decreased food intake without significant effect on body weight. GLP-1-(23) and GCGR Ab decreased RQ with GLP-1, causing a greater effect. In a hyperglycemic clamp, GLP-1-(23) reduced hepatic glucose production (HGP), increased glucose infusion rate (GIR), increased glucose uptake in brown adipose tissue, and increased whole-body glucose turnover, glycolysis, and rate of glycogen synthesis. GCGR Ab slightly decreased HGP, increased GIR, and increased glucose uptake in the heart. SiDMAP showed that GLP-1-(23) and GCGR Ab increased (13)C lactate labeling from glucose, indicating that liver, muscle, and other organs were involved in the rapid disposal of glucose from plasma. GCGR Ab and GLP-1-(23) caused different changes in mRNA expression levels of glucose- and lipid metabolism-associated genes. The effect of GLP-1-(23) on energy state and glucose homeostasis was greater than GCGR Ab. Although GCGR antagonism is associated with increased circulating levels of GLP-1, most GLP-1-(23)-associated pharmacologic effects are more pronounced than GCGR Ab.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc, Thousand Oaks, California 91320, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Narumol
authors.initials: N
authors.lastname: Chinookswong
authors.forename: Renée
authors.initials: R
authors.lastname: Komorowski
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: Melissa
authors.initials: M
authors.lastname: Graham
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Winters
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Boros
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lindberg
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D004041:Dietary Fats; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1