Early Low Fat Diet Enriched with Linolenic Acid Reduces Liver Endocannabinoid Tone and Improves Late Glycemic Control After a High Fat Diet Challenge in Mice.

Evidence suggests that alterations of glucose and lipid homeostasis induced by obesity are associated with elevation of endocannabinoid tone. The biosynthesis of the two main endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG), which derive from arachidonic acid, is influenced by dietary fatty acids (FA).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 either lard or lard + safflower oil or lard + 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 to 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 to reduce endocannabinoid tone and improve metabolic parameters in the metabolic syndrome.
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