Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice

Abstract

Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function. Methods Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.Results Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake. Conclusions/interpretation Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.

Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

“…High plasmatic levels of endocannabinoids have been associated with increased cardiometabolic risk, visceral WAT accumulation, and type 2 diabetes in obese patients ( 19 ). Genetic impairment of CB1 receptors selectively in neurons of the brain and sympathetic nervous system (SNS) enhances energy expenditure by the BAT ( 20 ), and very recent evidence suggests an inhibitory role of prejunctional CB1 on brown adipocyte glucose utilization ( 21 ), thermogenesis, and lipid droplet formation ( 22 ). Furthermore, CB1 blockade in Sim1-expressing neurons of the paraventricular nucleus of the hypothalamus enhances energy expenditure during high-fat diet feeding ( 23 ).…”

“…It is possible that chronic ␤ -adrenergic stimulation under cold exposure leads to the desensitization of those intracellular signals required to elevate endocannabinoid levels following an acute stimulation; whereas, instead, the effect on the expression of CB1 receptors requires prolonged stimulation of other ␤ 3-adrenoceptor-coupled intracellular signals. The reasons for these differences might also lie in the differential regulation of the expression of AEA and 2-AG metabolic enzymes account, in part, for the previously demonstrated enhancement of thermogenesis and energy expenditure by CB1 receptor inverse agonists, both in animal models of obesity ( 21,22 ) and in obese humans ( 31 ). In the BAT, cold was ineffective at elevating endocannabinoid signaling in a statistically signifi cant manner, and treatment of mice with CL had to be acute in order to achieve a statistically signifi cant elevation of 2-AG and/or AEA ( Fig.…”

Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages

“…CB1 activation in mouse and human WAT reduces mitochondrial mass and function by downregulation of PPARγ coactivator 1α (Ppargc1a), while genetic and pharmacological blockade of CB1 function increases mitochondrial biogenesis by enhancing Ppargc1a expression (24,25). Accordingly, body weight loss induced by chronic administration of CB1 antagonists is largely due to increased energy expenditure (EE) and consequent activation of lipolysis and fatty acid oxidation (21,(26)(27)(28). However, the therapeutic use of CB1 antagonists, such as rimonabant, is hampered by serious side effects, which include depression and anxiety, primarily caused by the action of this drug in the brain (29,30).…”

Intestinal lipid–derived signals that sense dietary fat

“…Activation of the CB 1 receptor subtype -which is particularly abundant in the brain and spinal cord, but is also spread throughout the rest of the body (13) -increases food intake, enhances reward aspects of eating, and promotes energy conservation (4,14). Conversely, pharmacological or genetic blockade of the receptor decreases feeding, sustains weight loss, heightens insulin sensitivity, and improves dysregulated lipid metabolism in both animal models and obese humans (14,15). Central and peripheral mechanisms cooperate to produce these effects.…”