The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co-evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter-gatherers and pastoralists with the high-carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB 2 ) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB 1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB 1 /CB 2 receptor activation ratio may thus play a role in the nutrition transition of Western high-calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed.
LINKED ARTICLESThis article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc Abbreviations 2-AG, 2-arachidonoyl glycerol; AA, arachidonic acid; AEA, N-arachidonoylethanolamine, anandamide; apoE, apolipoprotein E; BAT, brown adipose tissue; BCP, β-caryophyllene; CNR1, gene encoding CB 1 receptors; DHA, docosahexaenoic acid; DIM, 3,3 0 -diindolylmethane; EC, endocannabinoid; ECS, endocannabinoid system; EPA, eicosapentanoic acid; FAAH, fatty acid amide hydrolase; NAE, N-acylethanolamine; PEA, palmitoylethanolamide; PUFA, polyunsaturated fatty acid; SNP, single nucleotide polymorphism; T2DM, diabetes mellitus type 2; THC, Δ 9 -tetrahydrocannabinol; TRPV1, transient re- The endocannabinoid system (ECS) is an ancient panorgan eicosanoid signalling network in which arachidonic acid (AA) derived lipids act in concert with particular receptors and enzymes resulting in the complex modulation of numerous central and peripheral physiological and pathophysiological processes (Pertwee, 2005(Pertwee, , 2009Di Marzo, 2008a;Pacher and Mechoulam, 2011;DiPatrizio and Piomelli, 2015). The ECS comprises classical GPCR cannabinoid receptors (CB 1 and CB 2 ) and potentially also the orphan receptor GPR55 (Pertwee, 2007;Ryberg et al., 2007), which are differentially activated by the endocannabinoids (ECs) 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine ...