Table_1_Sex differences in endocannabinoids during 3 years of Mediterranean diet intervention: Association with insulin resistance and weight loss in a population with metabolic syndrome.XLSX

BackgroundExcess circulating endocannabinoids (eCBs) and imbalanced N-acylethanolamines (NAEs) related eCBs abundance could influence dietary weight loss success. We aimed to examine sex differences in the impact of a 3-years Mediterranean diet (MedDiet) intervention on circulating eCBs, NAEs and their precursor fatty acids, and to analyze the interplay between changes in eCBs or NAEs ratios, insulin resistance and the achievement of clinically meaningful weight reductions.
MethodsProspective cohort study in a subsample of N = 105 participants (54.3% women; 65.6 ± 4.6 years) with overweight or obesity and metabolic syndrome that underwent a 3-years MedDiet intervention (PREDIMED-Plus study). Plasma eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), fatty acids, diet, glycemic homeostasis (including the assessment of insulin resistance-HOMA-IR), and cardiovascular risk markers were monitored (at 0-6-12-36 months).
ResultsMediterranean diet adherence increased in both sexes and remained high during the 3 years of follow-up. Reductions in body weight, glycemic and cardiovascular parameters were larger in men than in women. Women presented higher concentrations of NAEs than men throughout the study. In both sexes, AEA and other NAEs (including OEA, and PEA) decreased after 6 months (for AEA: −4.9%), whereas the ratio OEA/AEA increased after 1 year (+5.8%). Changes in 2-AG (−3.9%) and the ratio OEA/PEA (+8.2%) persisted over the 3 years of follow-up. In women, 6-months changes in AEA (OR = 0.65) and the ratio OEA/AEA (OR = 3.28) were associated with the achievement of 8% weight reductions and correlated with HOMA-IR changes (r = 0.29 and r = −0.34). In men, OEA/PEA changes were associated with 8% weight reductions (OR = 2.62) and correlated with HOMA-IR changes (r = −0.32).
ConclusionA 3-years MedDiet intervention modulated plasma concentrations of eCBs and NAEs. Changes in AEA and in the relative abundance of NAEs were associated with clinically meaningful weight reductions. However, marked sex differences were identified in eCBs and NAEs, as well as in the efficacy of the intervention in terms of glycemic and cardiovascular parameters, which could be related to post-menopause alterations in glucose metabolism. These findings support a sex-balanced research strategy for a better understanding of the mechanisms underlying the regulation of body weight loss.

研究背景：循环中过量的内源性大麻素（endocannabinoids, eCBs）以及与eCBs丰度失衡相关的N-酰基乙醇胺（N-acylethanolamines, NAEs）水平紊乱，可能会影响饮食减重的成功率。本研究旨在探究3年地中海饮食（Mediterranean diet, MedDiet）干预对循环中eCBs、NAEs及其前体脂肪酸的影响是否存在性别差异，并分析eCBs或NAEs比值变化、胰岛素抵抗与达到具有临床意义的体重降幅之间的相互关联。
研究方法：本研究为前瞻性队列研究，分析对象为PREDIMED-Plus研究中接受3年MedDiet干预的105名超重/肥胖合并代谢综合征受试者（其中女性占54.3%，平均年龄65.6±4.6岁）。研究人员在基线、6、12及36个月时对受试者的血浆eCBs、NAEs水平（包括2-花生四烯酰甘油（2-arachidonoylglycerol, 2-AG）、花生四烯酸乙醇胺（anandamide, AEA）、油酰乙醇胺（oleoylethanolamide, OEA）以及棕榈酰乙醇胺（palmitoylethanolamide, PEA））、脂肪酸、膳食摄入、血糖稳态（包括胰岛素抵抗评估——稳态模型评估胰岛素抵抗指数（homeostasis model assessment of insulin resistance, HOMA-IR））以及心血管风险标志物进行检测。
研究结果：两性受试者的地中海饮食依从性均有所提升，并在3年随访期间维持在较高水平。男性受试者的体重、血糖及心血管指标降幅均大于女性。整个研究期间，女性受试者的NAEs浓度均高于男性。在两性受试者中，AEA及其他NAEs（包括OEA与PEA）的水平在6个月后均有所下降（AEA降幅为4.9%），而OEA/AEA比值在1年后升高（增幅为5.8%）。2-AG水平（降幅3.9%）及OEA/PEA比值（增幅8.2%）的变化在整个3年随访期间持续存在。在女性受试者中，6个月时AEA水平变化（比值比（odds ratio, OR）=0.65）与OEA/AEA比值变化（OR=3.28）均与达到8%的体重降幅相关，且与HOMA-IR变化呈显著相关（相关系数r分别为0.29与-0.34）。在男性受试者中，OEA/PEA比值变化与8%的体重降幅相关（OR=2.62），且与HOMA-IR变化呈显著相关（r=-0.32）。
研究结论：3年MedDiet干预可调节血浆中eCBs与NAEs的浓度水平。AEA水平及NAEs相对丰度的变化与具有临床意义的体重降幅存在关联。但本研究发现，eCBs与NAEs的水平、以及干预在血糖与心血管指标方面的疗效均存在显著性别差异，这可能与绝经后葡萄糖代谢的改变有关。上述研究结果提示，应采用性别均衡的研究策略，以更深入地阐明体重减轻调控的潜在机制。