title: Developmental role for endocannabinoid signaling in regulating glucose metabolism and growth.
abstract: Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve β-cell function and glucose homeostasis in the setting of leptin deficiency.
authors: Rockefeller University, New York, New York, USA.
authors: Zhiying
authors: Z
authors: Li
authors: Sarah F
authors: SF
authors: Schmidt
authors: Jeffrey M
authors: JM
authors: Friedman
mesh_terms: D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D007328:Insulin; D020738:Leptin; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D054411:Receptors, Leptin; D007334:Insulin-Like Growth Factor I; D005947:Glucose; D000077285:Rimonabant