Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?

Abstract

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 (CB₂ ) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB₁ receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB₁ /CB₂ 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 articles: This 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.

Figure 1

Hypothetical evolutionary model of the differential roles of CB₁ and CB₂ receptors in human (patho)physiology. The ECS integrates dietary stimuli from different lifestyles leading to a potential mismatch in agriculturist societies where high‐calorie food (sugars and fats) predominates. To compensate for the detrimental effects of chronic CB₁ receptor activation in peripheral organs, CB₂ receptors may have evolved as a protective mechanism. While both CB₁ and CB₂ receptors are protective in the GI tract (1), in the liver (2), kidney (3) and adipocytes (4), CB₂ receptor activation could counteract the pro‐obesity and pro‐fibrotic action of CB₁ receptor activation. In addition, CB₂ receptor activation may ameliorate chronic inflammation [e.g. via macrophage polarization (5)] and metabolic disease. Some phytochemicals introduced during agriculture (spices, leafy vegetables, etc.) may modulate the CB₁/CB₂ receptor activation ratio, thus linking diet with physiology.