Cannabinoid Type 1 Receptors are Upregulated During Acute Activation of Brown Adipose Tissue

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with up-regulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and decrease cardiometabolic risk factors. These effects may partly be mediated via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography (PET) radioligand [ F]FMPEP- , and in parallel measured BAT activation with the glucose analogue [ F]FDG. Activation by cold exposure markedly increased CB1R density and glucose uptake in BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1R provide a novel therapeutic target for BAT activation in humans.