Evidence suggests that alterations of glucose and lipid homeostasis induced by obesity are associated with the elevation of endocannabinoid tone. The biosynthesis of the two main endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoyl-glycerol, which derive from arachidonic acid, is influenced by dietary fatty acids (FAs). We investigated whether exposure to n-3 FA at a young age may decrease tissue endocannabinoid levels and prevent metabolic disorders induced by a later high-fat diet (HFD) challenge. Three-week-old mice received a 5% lipid diet containing lard, lard plus safflower oil, or lard plus linseed oil for 10 weeks. Then, mice were challenged with a 30% lard diet for 10 additional weeks. A low n-6/n-3 FA ratio in the early diet induces a marked decrease in liver endocannabinoid levels. A similar reduction was observed in transgenic Fat-1 mice, which exhibit high tissue levels of n-3 FA compared with wild-type mice. Hepatic expression of key enzymes involved in carbohydrate and lipid metabolism was concomitantly changed. Interestingly, some gene modifications persisted after HFD challenge and were associated with improved glycemic control. These findings indicate that early dietary interventions based on n-3 FA may represent an alternative strategy to drugs for reducing endocannabinoid tone and improving metabolic parameters in the metabolic syndrome.The endocannabinoid (EC) system (ECS) is known to play a crucial role in energy homeostasis. Regulation by this system takes place at the central level by changing food intake (1), and at the peripheral level by the modification of energy metabolism (2). An overactive ECS plays a crucial role in obesity by increasing food intake (3) and lipogenesis (4), by downregulating catabolic reactions (5,6), and by promoting fat accumulation and alteration of glucose homeostasis. As a consequence, treating obesity by decreasing ECS activity has been considered. A pharmacological approach was developed, leading to the commercialization of an inverse agonist of the cannabinoid receptor type-1 (CB1R) rimonabant. However, this drug was withdrawn from the market because of its undesired central nervous system side effects (7). Meanwhile, the downregulation of ECS tone in peripheral tissues involved in energy homeostasis, either with non-brain-penetrant CB1R blockers, or inhibitors of the biosynthesis of endogenous CB1R agonists, is still considered to be a potential approach to counter the adverse events observed in obesity (8).The ECS is defined as a set of endogenous ligands (ECs), synthesized and degraded by specific enzymes and receptors that are able to bind these molecules. It includes two membrane receptors, CB1R and CB2R, and two main endogenous agonists, N-arachidonoyl-ethanolamine (AEA [or anandamide]) and 2-arachidonoyl-glycerol (2-AG). AEA is typically synthesized by the enzyme N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), although alternative pathways

Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R, suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the antilipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test if the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.