Selective adipose blockade of CB1 receptor increases energy expenditure and reduces body weight
Obesity, particularly in childhood and adolescence, is the most relevant public health problem worldwide. Drug therapy of obesity is complex due to closed relationship between CNS and peripheral organs, so that many anti-obesity drugs have been withdrawn from market for diverse side effects. Obesity is caused by energy unbalance, with increased energy intake and decreased energy expenditure. Endocannabinoid system (ECS) includes two receptor types, CB1 and CB2, and many specific enzymes. CB1 receptor activation augments food consumption, while CB1 receptor blockade lowers food intake and body weight. Rimonabant, a selective CB1 receptor antagonist, has been used as a very effective anti-obesity drug; it has been withdrawn after depression and anxiety cases were observed in treated obese patients. CB1 receptor is expressed also in adipocytes, in which it controls energy homeostasis and lipid content. This study demonstrates that adipose CB1 genetic blockade (AtiCB1KO mice) transforms white adipose tissue (i.e., the tissue normally devoted to fat storage) into brown fat which is thermogenically active and able to dissipate energy as heat. In particular, genetic CB1 removal promotes M2 macrophage recruitment into adipose tissue. M2 macrophages are able to synthesize and release noradrenaline in adipose tissue, in addition to positively modulate sympathetic nervous system activity to fat. AtiCB1KO mice are, in fact, resistant to obesity due to high fat diet (HFD) consumption. Moreover, CB1 receptor silencing, when animals are already obese, reduces body weight, ameliorating their metabolic profile. Thus, specific molecules blocking adipose CB1 receptors and unable to cross blood-brain barrier may be of relevance for obesity drug treatment. These drugs would be free CNS side effects, and probably could be used in different disorders characterized by M2 macrophage involvement.
Ruiz de Azua et al., Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J Clin Invest. 127(11): 4148-4162, 2017. doi:10.1172/JCI83626.