Developmental Role for Endocannabinoid Signaling in Regulating Glucose Metabolism and Growth

摘要

Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnrl) 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 Cnrl knockout ob/ob mice. Double mutant animals show a more severe growth retardation than 06/06 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 06/06 mice. This is in contrast to treatment of 06/06 mice with a Cnrl 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 06/06 mice, suggesting that there are developmental changes that compensate for the loss of Cnrl signaling. These data establish a role for Cnrl during development and suggest that compensatory changes during development may mitigate the requirement for Cnrl in mediating the effects of leptin. The data also suggest a developmental role for Cnrl to promote growth, regulate the GH/IGF-I axis, and improve (3-cell function and glucose homeostasis in the setting of leptin deficiency.