It is well known that cannabinoid type 1 receptor (CB1) antagonist drugs may reduce body weight and improve metabolic profiles in obese animals and humans by a double mechanism: at first, targeting mesolimbic and hypothalamic nuclei and, thereafter, peripheral organs involved in energy storage and expenditure. However, it is still unknown which of these sites of action may have a predominant role in the endocannabinoid effect on energy balance regulation. To solve this question we generated a mouse line in which the CB1 coding region is flanked by two loxP sites (CB1f/f). By crossing this with mice that express Cre recombinase under the control of the regulatory sequences of the Ca2+/calmodulin-dependent Kinase IIa gene (CB1CaMKIIaCre mice), we obtained CB1f/f;CaMKIIaCre mice in which CB1 receptor is deleted in all principal neurons of the forebrains, including those at mesolimbic and hypothalamic level modulating the positive incentive to palatable food and the orexigenic signals, respectively. Here we show that adult male CB1CaMKIIaCre (n. 15 each group, age 1621 weeks for each diet) were still statistically significant leaner than the wild type littermates either undergoing standard diet or with high fat diet (40% kcal given by fat). However, when cumulative food intake was investigated, adult male CB1CaMKIIaCre mice did not show any statistically significant difference in caloric intake as compared to wild types with both diets. These data seem to indicate that other neuronal pathways may overcome the lack of the central CB1 orexigenic drive; on the other hand, it may suggest that CB1 may still play a crucial role at cerebral level as a sensor of yet unknown peripheral signals involved in energy homeostasis.
28 Apr - 02 May 2007
European Society of Endocrinology