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

Abstract

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 (Cb2 −/− [also known as Cnr2]) were studied at different ages (2-12 months). Twomonth-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.

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

“…This is consistent with our previous findings that systemic or local administration of JWH133 into the nucleus accumbens inhibits cocaine self-administration (22), and that transgenic up-regulation of brain CB 2 Rs attenuates cocaine self-administration and cocaine-induced increased locomotion (19). The present findings are also congruent with recent reports that brain CB 2 Rs have important roles in other DArelated functions and/or CNS disorders (12,25,51,52).…”

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

“…Here we have mostly reviewed information on the roles of anandamide, 2-AG and CB 1 R in energy balance; however, it should be mentioned that some evidence suggests an involvement for CB 2 R in energy balance (139,140,141) and that compounds structurally related to endocannabinoids but unable to bind to CB 1 R, like oleoylethanolamide (OEA), actually oppose endocannabinoids effects on energy balance (142). Besides, endocannabinoids do not exclusively exert their biological functions through CBRs, however they can also bind transient receptor potential vanilloid 1 (TRPV1) (143) and the nuclear receptor peroxisome proliferatoractivated receptor γ (PPARγ) (56).…”

Endocannabinoids and Metabolic Disorders

“…Moreover, CB 2 receptors have also recently emerged as a potential target for the treatment of certain metabolic disorders. Indeed, as has been briefly mentioned already, CB 2 receptor activation favors hepatic steatosis and insulin resistance, most likely by reducing heightened inflammatory responses, since CB 2 receptors are expressed on immune cells (Deveaux et al 2009;Agudo et al 2010). However, additional work is needed in order to exactly understand the function of CB 2 receptors or of other receptors that can be activated by endocannabinoids, such as transient receptor potential vanilloid 1 (TRPV1) and PPARs, in the context of endocannabinoid-dependent regulation of energy balance and metabolism.…”