title: Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.
abstract: Leptin and glucagon-like peptide 1 (GLP-1) exhibit opposing actions in the endocrine pancreas. GLP-1 stimulates insulin biosynthesis, secretion, and islet growth, whereas leptin inhibits glucose-dependent insulin secretion and insulin gene transcription. In contrast, GLP-1 and leptin actions overlap in the central nervous system, where leptin has been shown to activate GLP-1 circuits that inhibit food intake. To determine the physiological importance of GLP-1 receptor (GLP-1R)-leptin interactions, we studied islet function and feeding behavior in ob/ob:GLP-1R(-/-) mice. Although GLP-1R actions are thought to be essential for glucose-dependent insulin secretion, the levels of fasting glucose, glycemic excursion after glucose loading, glucose-stimulated insulin, and pancreatic insulin RNA content were similar in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R(-/-) mice. Despite evidence linking GLP-1R signaling to the regulation of islet neogenesis and proliferation, ob/ob:GLP-1R(-/-) mice exhibited significantly increased islet numbers and area and an increase in the number of large islets compared with GLP-1R(+/+) or (-/-) mice (P < -0.01 to 0.05). Similarly, growth rates and both shortand long-term control of food intake were comparable in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R4(-/-) mice. Furthermore, leptin produced a similar inhibition of food intake in GLP-1R(-/-), ob/ob:GLP-1R(+/+), and ob/ob:GLP1R4(-/-) mice. These findings illustrate that although leptin and GLP-1 actions overlap in the brain and endocrine pancreas, disruption of GLP-1 signaling does not modify the response to leptin or the phenotype of leptin deficiency in the ob/ob mouse, as assessed by long-term control of body weight or the adaptive beta-cell response to insulin resistance in vivo.
authors.affiliation: Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Ontario, Canada.
authors.forename: L A
authors.initials: LA
authors.lastname: Scrocchi
authors.forename: M E
authors.initials: ME
authors.lastname: Hill
authors.forename: J
authors.initials: J
authors.lastname: Saleh
authors.forename: B
authors.initials: B
authors.lastname: Perkins
authors.forename: D J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D002455:Cell Division; D003433:Crosses, Genetic; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005934:Glucagon / Q000097:blood / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006579:Heterozygote; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D010446:Peptide Fragments / Q000097:blood / Q000502:physiology*; D011498:Protein Precursors / Q000097:blood / Q000502:physiology*; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D012727:Sex Characteristics; D015398:Signal Transduction; D015430:Weight Gain / Q000502:physiology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D020738:Leptin; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D052216:Glucagon-Like Peptide 1; D005934:Glucagon