Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age

Aims/hypothesis The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism. Methods Mice deficient in CB2R (Ch2(-/-) [also known as Cnr2]) were studied at different ages (2-12 months). Two-month-old Cb2(-/-) and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet. Results The lack of CB2R in Cb2(-/-) mice led to greater increases in food intake and body weight with age than in Cb2(+/+) mice. However, 12-month-old obese Cb2(-/-) mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2(-/-) mice were fed a high-fat diet, reduced body weight gain and normal insulin sensitivity were observed. Conclusions/interpretation These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance.