Leptin sensitivity in nonobese glucagon-like peptide I receptor -/- mice.
Glucagon-like peptide I (GLP-I) stimulates glucose-dependent insulin secretion and inhibits food intake in the central nervous system. Because leptin reduces food intake but inhibits insulin secretion, we examined leptin action in mice with a null mutation in the GLP-I receptor. Intracerebroventricular leptin administration inhibited food intake in both wild-type and GLP-I receptor (GLP-IR) -/- mice, and daily intraperitoneal administration of leptin for 2 weeks produced comparable reductions in food intake and body weight in control and GLP-IR -/- mice. Glucose tolerance was improved in both wild-type and GLP-IR -/- mice, whether pair fed or leptin treated; however, blood sugars were significantly lower in the leptin-treated GLP-IR -/- mice following oral glucose challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and leptin-treated mice (P < 0.01-0.001); however, insulin levels were significantly lower in leptin-treated versus pair-fed GLP-IR -/- mice (P < 0.01). A single leptin injection had no effect on glucose tolerance in GLP-IR -/- mice, but decreased hepatic PEPCK mRNA in both wild-type and GLP-IR -/- mice. The improvement in blood glucose excursion, despite lower levels of glucose-stimulated insulin in lean leptin-treated GLP-IR -/- mice, suggests that leptin may have beneficial effects on control of blood glucose in the absence of obesity. Furthermore, the greater effects of leptin on glucose and insulin in leptin-treated versus pair-fed GLP-IR -/- mice raises the possibility that disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.
Scrocchi
L A
LA
Department of Medicine, Banting and Best Diabetes Centre, The Toronto Hospital, University of Toronto, Canada.
Brown
T J
TJ
Drucker
D J
DJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D020738:Leptin; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics* / Q000502:physiology; D054411:Receptors, Leptin; D015398:Signal Transduction
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D010729:Phosphoenolpyruvate Carboxykinase (GTP)