title: Absence of the glucagon-like peptide-1 receptor does not affect the metabolic phenotype of mice with liver-specific G(s)α deficiency.
abstract: The stimulatory G protein α-subunit (G(s)α) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver-specific G(s)α deficiency [liver-specific G(s)α knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon-like peptide 1 (GLP-1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r(-/-)) and compared LGsKO to double-knockout (LGs/Glp1r(-/-)) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific G(s)α deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver G(s)α/cAMP pathway and pancreatic islet function need to be further elucidated.
authors.affiliation: Metabolic Diseases Branch, Building 10 Room 8C101, National Institute for Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA. minc@intra.niddk.nih.gov
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Eralda
authors.initials: E
authors.lastname: Mema
authors.forename: James
authors.initials: J
authors.lastname: Kelleher
authors.forename: Nicholas
authors.initials: N
authors.lastname: Nemechek
authors.forename: Alta
authors.initials: A
authors.lastname: Berger
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000502:physiology; D001823:Body Composition / Q000502:physiology; D004435:Eating / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D019205:GTP-Binding Protein alpha Subunits, Gs