The Effects of Rimonabant on Brown Adipose Tissue in Rat: Implications for Energy Expenditure

Abstract

The cannabinoid CB1 receptor antagonist rimonabant (SR 141716) produces a sustained decrease in body weight on a background of a transient reduction in food intake. An increase in energy expenditure has been implicated, possibly mediated via peripheral endocannabinoid system; however, the role of the central endocannabinoid system is unclear. The present study investigates this role. Rimonabant (10 mg/kg IP) was administered for 21 days to rats surgically implanted with biotelemetry devices to measure temperature in the interscapular brown adipose tissue (BAT). BAT temperature as a putative measure of thermogenesis in the BAT, physical activity, body weight, food intake, as well as changes in UCP1 messenger RNA (mRNA) and protein were measured. In addition, role of the CNS in mediating these actions of rimonabant was determined in rats where the BAT was sympathetically denervated. As expected, chronic administration of rimonabant significantly reduced body weight for the entire treatment period despite only a transient decrease in food intake. There was a profound increase in BAT temperature, particularly during the dark phase of each circadian cycle throughout the treatment period. A corresponding increase in uncoupling protein (UCP1) was also observed following chronic rimonabant treatment. The rimonabant‐induced elevation in BAT temperature and decrease in body weight were significantly attenuated following denervation, indicating an involvement of the CNS. These findings suggest that the long‐term weight loss associated with rimonabant treatment is due at least in part to an elevation in energy expenditure, represented here by elevated temperature recorded in the BAT, which is mediated primarily by the central endocannabinoid system.

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

“…Energy expenditure enhanced by blockade of central CB1 antagonists is primarily mediated by sympathetic activation via central nervous system action. 6,7,31 In contrast to rimonabant, acute treatment with BPR697 did not elevate energy expenditure, which is well correlated with its poor central nervous system penetration. This result indicates the weight loss from BPR697 is not due to enhancement of energy expenditure.…”

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…In a recent study by Verty et al, 50 rimonabant-induced BAT (brown adipose tissue) temperature increase was eliminated when BAT was sympathetically denervated. These data indicate that the rimonabantinduced energy expenditure increase in BAT requires intact communication between the brain and periphery, and BAT temperature increase is likely mediated by rimonabant acting on CNS CB1R.…”

Counterregulation of insulin by leptin as key component of autonomic regulation of body weight

“…Olfactory responsiveness [68] and hedonic responses to food and associated increases in DIT [67] show a diurnal rhythm with an acrophase during the active portion of the circadian period. The rhythm and the magnitude of thermogenic response are abolished by SCN lesion, sympathetic denervation of BAT [66] , or deletion of β1 receptors in BAT [60] . Endocannabinoid blockade of DIT thermogenesis is more effective during the active that during the inactive phase of the circadian cycle [66] .…”