Circulating endocannabinoids in insulin sensitive vs. Insulin resistant obese postmenopausal women. A MONET group study

Abstract

Objective: To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women. Design and Methods: The sample consisted of 30 obese postmenopausal women (age: 58.9 6 5.2 yrs; BMI: 32.9 6 3.6 kg/m 2 ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 6 3.3 mg min 21 kg 21 FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry. Results: IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05). Conclusions: This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-a ligand.

Modulation of plasma N-acylethanolamine levels and physiological parameters by dietary fatty acid composition in humans

“…This effect of OEA on feeding behavior and bodyweight gain is also replicated with PEA, but with less potency, potentially through increased leptin sensitivity ( 7,9 ). Similarly, overweight/obese T2D patients have increased circulating levels of AEA and 2-arachidonoylglycerol (2-AG), an AEA-related endocannabinoid, as well as increased subcutaneous white adipose tissue AEA levels confi rming the link between AEA levels and adiposity and also suggesting a link between AEA levels and insulin resistance ( 10,11 ). The reactive roles of endocannabinoids and their response to energy balance are well established; however, the important impact of diet fat selection as proactive precursors to circulating endocannabinoids and their role in metabolic control are still widely unknown ( 12,13 ).…”

The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease

“…Plasma endocannabinoids correlate positively with markers of obesity and metabolic disorder, such as body mass index, waist circumference, visceral fat mass, and insulin resistance [80][81][82][83][84][85]. However, it is not known whether circulating endocannabinoids simply reflect spillover from sites of production, or participate in signaling events that might in turn affect feeding and metabolism.…”

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

“…Endocannabinoids can be detected in the circulation and their assessment from blood samples is a simple strategy used for the study of the ECS. Notwithstanding the limitations of this approach related to differences in the handling, preparation or extraction of the sample among different laboratories and due to the lack of 'normal' range reference levels, several studies have shown positive association of plasma endocannabinoids with markers of obesity and metabolic disorder (53,99,100,101,102). Increased plasma endocannabinoids have been also found in obese subjects affected by Prader-Willi syndrome (103), in which treatment with rimonabant proved effective in reducing weight (104).…”