Profiling plasma N-Acylethanolamine levels and their ratios as a biomarker of obesity and dysmetabolism

Abstract

ObjectiveN-acylethanolamines play different roles in energy balance; anandamide (AEA) stimulates energy intake and storage, N-palmitoylethanolamide (PEA) counters inflammation, and N-oleoylethanolamide (OEA) mediates anorectic signals and lipid oxidation. Inconsistencies in the association of plasma N-acylethanolamines with human obesity and cardiometabolic risk have emerged among previous studies, possibly caused by heterogeneous cohorts and designs, and by unstandardized N-acylethanolamine measurements. We aimed to characterize changes in the plasma profile, including N-acylethanolamine levels and ratios associated with obesity, menopause in women, and ageing in men, and to define the significance of such a profile as a biomarker for metabolic imbalance.MethodsAdult, drug-free women (n = 103 premenopausal and n = 81 menopausal) and men (n = 144) were stratified according to the body mass index (BMI) into normal weight (NW; BMI: 18.5–24.9 kg/m2), overweight (OW; BMI: 25.0–29.9 kg/m2), and obese (OB; BMI ≥30.0 kg/m2). Anthropometric and metabolic parameters were determined. Validated blood processing and analytical procedures for N-acylethanolamine measurements were used. We investigated the effect of BMI and menopause in women, and BMI and age in men, as well as the BMI-independent influence of metabolic parameters on the N-acylethanolamine profile.ResultsBMI and waist circumference directly associated with AEA in women and men, and with PEA in premenopausal women and in men, while BMI directly associated with OEA in premenopausal women and in men. BMI, in both genders, and waist circumference, in women only, inversely associated with PEA/AEA and OEA/AEA. Menopause increased N-acylethanolamine levels, whereas ageing resulted in increasing OEA relative abundance in men. AEA and OEA abundances in premenopausal, and PEA and OEA abundances in lean menopausal women, were directly associated with hypertension. Conversely, PEA and OEA abundances lowered with hypertension in elderly men. Insulin resistance was associated with changes in N-acylethanolamine ratios specific for premenopausal (reduced PEA/AEA and OEA/AEA), menopausal (reduced OEA/AEA) women and men (reduced OEA/AEA and OEA/PEA). PEA and OEA levels increased with total cholesterol, and OEA abundance specifically increased with HDL-cholesterol. Elevated triglyceride levels were associated with increased N-acylethanolamine levels only in menopausal women.ConclusionsObesity-related N-acylethanolamine hypertone is characterized by imbalanced N-acylethanolamine ratios. The profile given by a combination of N-acylethanolamine absolute levels and ratios enables imbalances to be identified in relationship with different metabolic parameters, with specific relevance according to gender, menopause and age, representing a useful means for monitoring metabolic health. Finally, N-acylethanolamine system appears a promising target for intervention strategies.

Endocannabinoids, endocannabinoid-like molecules and their precursors in human small intestinal lumen and plasma: does diet affect them?

“…In agreement with Balvers and co-workers, we found that total plasmatic NAPEs were about 13-to 32-fold higher than NAEs [57] and were more abundant in OB than NW and OW. Plasma concentrations of ECs and NAEs in the ileostomy cohort (average BMI 26.9 ± 0.9) were in the same order of magnitude to those previously measured in overweight and obese subjects with intact GI tracts [19,28,29,32]. In contrast, we did not find any association between 2-AG and AEA with BMI and this is consistent with the reported heterogeneity of observations in the literature, whereby plasma 2-AG has been positively correlated with BMI [25,26] and yet no in other studies [19,58].…”

“…Mounting evidence in subjects with inflammatory bowel disease and obesity indicates that circulating ECs are key mediators in the interplay between gut, microbiota and metabolic health [19][20][21][22][23]. Moreover, plasma ECs and NAEs are considered biomarkers of white adipose tissue distribution and insulin resistance in obesity [24][25][26][27][28][29][30][31][32] and, as NAPEs, they are tightly connected with diet, especially dietary fat [1] but also proteins [33,34].…”

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

“…Moreover, the relative abundance of some bacterial families, such as Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae, were independently correlated with the blood levels of several members of the NAE or 2-MAG families of lipids. Adiposity measures have been previously reported as strong correlates of circulating levels of endocannabinoids 13,17,18 . We corroborate these findings and we further demonstrate that their congeners, except OEA, are also correlated with body composition and fat distribution.…”

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

“…[12][13][14] Palmitoylethanolamide (PEA, C16:0), an endogenous PPAR-α agonist, has shown to have a bi-faced pharmacological profile. 17 Here, we have investigated PEA metabolic activities in liver, focusing on glucose and lipid homeostasis in a mouse model of diet-induced obesity. 17 Here, we have investigated PEA metabolic activities in liver, focusing on glucose and lipid homeostasis in a mouse model of diet-induced obesity.…”

“…Indeed, beyond the well-known analgesic and anti-inflammatory effects, 15 PEA shows a metabolic activity, modulating energy balance in animals 16 and humans. 17 Here, we have investigated PEA metabolic activities in liver, focusing on glucose and lipid homeostasis in a mouse model of diet-induced obesity. Moreover, our mechanistic study provides evidence for a central role of AMP kinase (AMPK) in PEA-induced adaptive metabolic setting.…”