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

Leptin and glucagon-like peptide 1 (GLP-1) exhibit opposing actions in the endocrine pancreas. GLP-1 stimulates insulin biosynthesis, secretion, and i slet growth, whereas leptin inhibits glucose-dependent insulin secretion an d 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 import ance of GLP-1 receptor (GLP-1R)-leptin interactions, we studied islet funct ion and feeding behavior in ob/ob:GLP-1R(-/-) mice. Although GLP-1R actions are thought to be essential for glucose-dependent insulin secretion, the l evels 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 short and lo ng-term control of food intake were comparable in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R(-/-) mice. Furthermore, leptin produced a similar inhibition o f food intake in GLP-1R(-/-), ob/ob:GLP-1R(+/+), and ob/ob:lep-1R(-/-) 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 adapti ve p-cell response to insulin resistance in vivo.