Overexpression of Cannabinoid CB2 Receptor in the Brain Induces Hyperglycaemia and a Lean Phenotype in Adult Mice

It is well known that the endocannabinoid system, through cannabinoid CB1 receptor activation, has an important role in the main aspects of energy balance (i.e. food intake, energy expenditure and glucose and fat metabolism), orchestrating all the machinery involved in body weight control and energy homeostasis. A number of studies have revealed a crucial role of brain CB1 receptors in these processes. However, functional cannabinoid CB2 receptors have also been described in the brain, with no studies addressing their putative role in body weight control and glucose homeostasis. We have tested this hypothesis by analysing fasting-induced feeding, body weight, some hypothalamic neuropeptides, glucose tolerance and plasma hormones in an animal model specifically overexpressing CB2 receptors in the central nervous system. We found that specific overexpression of CB2 receptors in the brain promoted higher basal glucose levels, decreased fasting-induced feeding and, eventually, led to a lean phenotype and glucose intolerance. These findings could not be attributed to decreased locomotor activity, increased anxiety or depressive-like behaviours. The expression of relevant neuropeptides such as pro-opiomelanocortin and galanin in the arcuate nucleus of the hypothalamus was altered but not those of the CB1 receptor. Indeed, no changes in CB1 expression were found in the liver, skeletal muscle and adipose tissue. However, cannabinoid CB1 and CB2 receptor expression in the endocrine pancreas and glucagon plasma levels were decreased. No changes in plasma adiponectin, leptin, insulin and somatostatin were found. Taken together, these results suggest a role for central cannabinoid CB2 receptors in body weight control and glucose homeostasis.