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 However, this drug was withdrawn from the market because of its undesired central nervous system side effects (7).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
Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1β secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1β is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1β sustains tumor growth recovery in 5-FU-treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anticancer and anti-inflammatory properties, which could improve 5-FU chemotherapy. Here, we demonstrate that DHA inhibits 5-FU-induced IL-1β secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1β concentration and tumor recurrence in 5-FU-treated tumor-bearing mice. Treatment with 5-FU led to JNK activation through ROS production in MDSC. JNK inhibitor SP600125 as well as DHA-mediated JNK inactivation decreased IL-1β secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to β-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through β-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1β release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1β form. Finally, we found a negative correlation between DHA content in plasma and the induction of caspase-1 activity in HLA-DR − CD33 + CD15 + MDSC of patients treated with 5-FU-based chemotherapy, strongly suggesting that our data are clinical relevant. Together, these data provide new insights on the regulation of IL-1β secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.
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