Plasma 2-arachidonoylglycerol is a biomarker of age and menopause related insulin resistance and dyslipidemia in lean but not in obese men and women

Abstract

Objective: The endocannabinoid system hypertonicity features obesity. Excess circulating 2-arachidonoylglycerol was variously associated with obesity-related metabolic impairment; however, unstandardized experimental and analytical settings have clouded its usefulness as a dysmetabolism biomarker. We aimed at assessing the influence of body mass index (BMI), menopause in women, and aging in men on 2-arachidonoylglycerol relationship with metabolic parameters.

Methods: Adult, unmedicated women (premenopausal (preMW): n = 103; menopausal (MW): n = 81) and men (n = 144) were stratified in 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) classes. Anthropometric and metabolic parameters were determined. Plasma 2-arachidonoylglycerol was measured by a validated liquid chromatography-mass spectrometry assay.

Results: 2-arachidonoylglycerol level was raised by menopause (P < 0.001) and by obesity in preMW (P < 0.001) and in men (P = 0.019). In the overall cohorts, 2-arachidonoylglycerol displayed BMI-independent relationships with dyslipidemia (preMW, MW and men), insulin resistance (MW and men), and hypertension (men), but not with waist circumference. Within preMW BMI classes, 2-arachidonoylglycerol correlations were found with triglycerides (P = 0.020) and total cholesterol (TC; P = 0.040) in OB women. In MW, 2-arachidonoylglycerol correlation with triglycerides was found in NW (P = 0.001) and OW (P = 0.034), but not in OB class. Moreover, we found 2-arachidonoylglycerol correlations with TC (P = 0.003), glucose (P < 0.001), and HOMA-IR (P = 0.035) specific for NW MW class. In men, 2-arachidonoylglycerol correlated with triglycerides in NW, OW (both P < 0.001), and OB (P = 0.029), with SBP (P = 0.023) and diastolic BP (DBP; P = 0.048) in OB, and with TC (P < 0.001) in OW class. In NW class 2-arachidonoylglycerol correlations were found with insulin (P = 0.003) and HOMA-IR (P = 0.001), both enhanced by aging (both P = 0.004), and with glucose (P = 0.015) and HDL (P = 0.004).

Conclusions: Plasma 2AG is a biomarker of clustering metabolic dysfunctions, especially in lean men and menopausal women, and could be of help in identifying subjects with elevated cardiometabolic risk despite a healthy anthropometric appearance.

Keywords: 1AG, 1-arachidonoylglycerol; 2-Arachidonoylglycerol; 2AG, 2-arachidonoylglycerol; Aging; BMI, body mass index; DBP, diastolic blood pressure; Dysmetabolism; EC, endocannabinoid; ECS, endocannabinoid system; Endocannabinoid system; HDL, high density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; Int, interaction; LC-MS/MS, liquid chromatography-tandem mass spectrometry; Menopause; NW, normal weight; OB, obese; OW, overweight; Obesity; SBP, systolic blood pressure; SD, standard deviation.

Figure 1

2-Arachidonoylglycerol (2AG) levels (Mean ± SD) according to body mass index in premenopausal and menopausal females (A) and in males (B) (Two-way ANOVA). ^aP < 0.001: OB vs. NW premenopausal women; ^bP < 0.001: OB vs. OW premenopausal women; ^cP = 0.019: OB vs. NW men; ^dP = 0.031: OB vs. OW men. No significant differences were found by comparing pairs of BMI classes within menopausal women (OW vs. NW: P = 0.551; OB vs. NW: P = 0.504; OB vs. OW: P = 0.874) and by comparing OW vs. NW premenopausal women (P = 0.626), as well as no significant difference was found in OW vs. NW men (P = 0.747).