Role of the endocannabinoid system in obesity induced by neuropeptide y overexpression in noradrenergic neurons

Objective: Endocannabinoids and neuropeptide Y (NPY) promote energy storage via central and peripheral mechanisms. In the hypothalamus, the two systems were suggested to interact. To investigate such interplay also in non-hypothalamic tissues, we evaluated endocannabinoid levels in obese OE-NPY^D?H mice, which overexpress NPY in the noradrenergic neurons in the sympathetic nervous system and the brain. Methods: The levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were measured in key regulatory tissues, that is, hypothalamus, pancreas, epididymal white adipose tissue (WAT), liver and soleus muscle, over the development of metabolic dysfunctions in OE-NPY^D?H mice. The effects of a 5-week treatment with the CB1 receptor inverse agonist AM251 on adiposity and glucose metabolism were studied.Results:2-AG levels were increased in the hypothalamus and epididymal WAT of pre-obese and obese OE-NPY^D?H mice. Anandamide levels in adipose tissue and pancreas were increased at 4 months concomitantly with higher fat mass and impaired glucose tolerance. CB1 receptor blockage reduced body weight gain and glucose intolerance in OE-NPY^D?H to the level of vehicle-treated wild-type mice.Conclusions:Altered endocannabinoid tone may underlie some of the metabolic dysfunctions in OE-NPY^D?H mice, which can be attenuated with CB1 inverse agonism suggesting interactions between endocannabinoids and NPY also in the periphery. CB1 receptors may offer a target for the pharmacological treatment of the metabolic syndrome with altered NPY levels.