Endocrine Abstracts

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 This is an important clinical issue since the CB₁ antagonist drugs have recently been withdrawn from the market due to their psychiatric side effects, and novel drugs selectively acting at peripheral level are now under investigation.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.