Aims: Recently, the endocannabinoid system emerged as a pivotal regulator of food intake, ingestive behavior and energy metabolism, acting through CB1 and its endogenous ligands, the endocannabinoids. CB1 antagonists may reduce body weight and improve metabolic profiles in animals and humans by a double mechanism: at first, they target mesolimbic and hypothalamic nuclei and, thereafter, peripheral organs involved in energy storage and expenditure. Nevertheless, it is still unknown how the ECS can exploit its action on these sites and how it can integrate all the outcomes in order to regulate energy balance.
Methods: Firstly, we generated a mouse line (CB1f/f;CaMKIIaCre) in which the CB1 gene was conditionally disrupted only at level of principal neurons of the forebrain, including mesolimbic and hypothalamic neuronal populations modulating the incentive value to palatable food and the orexigenic signals, respectively. Then, we measured growth and food intake in conditional and whole knock-out mice (CBN), on standard diet and high fat diet, and assessed body fat distribution by microCT scans. Moreover, we explored several pathways included endocannabinoid biosynthesis/degradation, hormonal secretion, inflammation and fatty acids production by Real-Time PCR in peripheral organs, such as white adipose tissue, liver and skeletal muscle.
Results: Our results showed that both CB1 whole and conditional CB1 knock-out mice were lighter than their control, without affecting food intake. MicroCT scans explained this difference in body weight showing a significant reduction in fat mass of both models and this discrepancy was highlighted in HFD. Moreover, Real-Time PCR analysis showed different gene expression profile between CBN, CB1f/f;CaMKIIaCre mice and their controls, in particular of those genes involved in lipogenic and metabolic pathways, suggesting that other mechanisms may overcome the central CB1 orexigenic effect in maintaining body weight reduced.
03 - 07 May 2008
European Society of Endocrinology