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: Min Chen, Eralda Mema, James Kelleher, Nicholas Nemechek, Alta Berger, Jie Wang, Tao Xie, Oksana Gavrilova, Daniel J Drucker, Lee S Weinstein
• Journal: Endocrinology (Endocrinology) Vol. 152 Issue 9 Pg. 3343-50 (Sep 2011) ISSN: 1945-7170 [Electronic] United States
• PMID: 21771891 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Insulin
• Receptors, Glucagon
• Glucagon-Like Peptide 1
• GTP-Binding Protein alpha Subunits, Gs

Topics

• Animals
• Basal Metabolism (physiology)
• Body Composition (physiology)
• Eating (physiology)
• GTP-Binding Protein alpha Subunits, Gs (genetics, metabolism)
• Glucagon-Like Peptide 1 (genetics, metabolism)
• Glucagon-Like Peptide-1 Receptor
• Glucose Tolerance Test
• Insulin (metabolism)
• Islets of Langerhans (metabolism)
• Liver (metabolism)
• Mice
• Mice, Transgenic
• Phenotype
• Receptors, Glucagon (genetics, metabolism)