Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

Abstract

The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2‑MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC–MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2‑MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2‑MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.

Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists

“…The ability of this latter complex system to influence central and peripheral functions such as appetite, feeding behavior, and energy balance has recently received considerable attention, particularly in the light of metabolic disorders such as metabolic syndrome [ 23 , 25 , 68 , 69 ]. Since these same metabolic functions are under the influence of the intestinal microbiota, the scientific community has been paying increasing interest in the potential cross-talk between the eCBome, the gut microbiome, particularly during gut dysbiosis in the context of obesity [ 28 , 33 , 40 ].…”

“…Increasing evidence has suggested that obesity and related complications are associated with an altered eCBome both in mice models and in humans [ 13 , 23 , 28 , 29 , 30 , 31 , 32 ]. For instance, individuals with increased visceral fat mass exhibited increased levels of MAGs, while levels of some NAEs were shown to be higher in individuals with overall elevated adiposity [ 33 ]. Furthermore, obesity is characterized by CB 1 upregulation in the liver and intestine [ 34 , 35 , 36 , 37 ].…”

Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models

“…Previous studies have demonstrated in mice that this hormone negatively regulates the hypothalamic biosynthesis of orexigenic eCBs (i.e., AEA and 2-AG), thus further contributing to appetite inhibition [ 56 , 57 ]. Accordingly, reduced leptin sensitivity might subsequently lead to higher levels of AEA, which one recent report showed to be positively correlated to other NAEs, including EPEA and DHEA, using PCA in a heterogeneous population [ 11 ]. However, we did not have a healthy control group to confirm the occurrence of leptin resistance in our obese patients.…”

“…In pathological conditions such as obesity, the levels of some of these mediators are altered in the blood and in several organs such as the liver, the brain or the intestine [ 7 , 8 , 9 , 10 ]. For example, levels of some NAEs were shown to be higher in individuals with elevated fat mass (FM), while increased levels of MAGs were found in individuals characterized by preferentially visceral fat distribution [ 11 ]. Obesity-related alterations in the eCB system are associated with excessive CB 1 activation, which may favor increased food intake, mitigation of energy expenditure, and accumulation of fat in the adipose tissue [ 10 , 11 , 12 ].…”

“…For example, levels of some NAEs were shown to be higher in individuals with elevated fat mass (FM), while increased levels of MAGs were found in individuals characterized by preferentially visceral fat distribution [ 11 ]. Obesity-related alterations in the eCB system are associated with excessive CB 1 activation, which may favor increased food intake, mitigation of energy expenditure, and accumulation of fat in the adipose tissue [ 10 , 11 , 12 ]. On the other hand, eCBome mediators such as PEA, OEA, 2-OG, and 2-LG may influence energy metabolism by activating non-cannabinoid receptors such as peroxisome proliferator-activated receptor (PPAR) α, transient receptor potential cation channel subfamily V member 1 (TRPV1), G protein-coupled receptor 55 (GPR55) and 119 (GPR119) [ 13 , 14 , 15 , 16 , 17 ].…”