ESE Young Investigator Award
Carmelo Quarta1, Luigi Bellocchio2, Giacomo Mancini3, Roberta Mazza1, Daniela Cota2, Lutzie J Braulke4, Csaba Fekete5,6, Enzo Nisoli7,8, Renato Pasquali1, Beat Lutz3, Giovanni Marsicano2 & Uberto Pagotto1
The pharmacological blockade of cannabinoid receptor type 1 (CB1) has been shown to counteract diet induced obesity (DIO). An unsolved question is whether the effects of CB1 blockade on energy balance are due to peripheral or central mechanisms. This is an important clinical issue since the CB1 antagonist drugs have recently been withdrawn from the market due to their psychiatric side effects, and novel drugs selectively acting at peripheral level are now under investigation. To unveil the differential role of brain versus peripheral CB1 in the control of DIO, we characterized conditional mutant mice lacking the expression of CB1 only in forebrain neurons (CaMK-CB1-KO mice), comparing their phenotype to those of complete CB1-KO and wild-type mice. The systemic administration of rimonabant (a drug antagonizing both central and peripheral CB1) did not affect metabolic functions in CaMK-CB1-KO mice, whether on standard (SD) or high fat diet (HFD). CB1 expression demonstrated to be knocked-out at central level (hypothalamus, nucleus of solitary tract) and preserved in peripheral organs of CaMK-CB1-KO mice. The analysis of the phenotype revealed that CaMK-CB1-KO mice were leaner than WT whether on SD or HFD; interestingly CaMK-CB1-KO mice on HFD displayed a metabolic profile (plasma levels of leptin, insulin, glucose, free fatty acids, circulating and intrahepatic triglycerides) and fat content (measured by CT-scan) undistinguishable from CB1-KO mice. By measuring energy expenditure we found that CB1 deletion in forebrain neurons influences metabolized energy and lipid utilization under HFD. These effects occurred by an increased brown adipose tissue function activated by the sympathetic nervous system (SNS), as demonstrated by in vivo PET analysis of BAT activity of CaMK-CB1-KO mice before and after sympathectomy. These data indicate that the forebrain CB1 receptor plays a key regulatory role in SNS activity and thus regulates energy balance in the body.