Peripheral Endocannabinoids Associated with Energy Expenditure in Native Americans of Southwestern Heritage

Context: The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as the related acylethanolamide oleoylethanolamide (OEA), have been implicated in energy expenditure (EE) regulation and metabolic diseases. Muscle (fat-free mass) and fat (fat mass) are metabolically active compartments and main determinants of EE. Objective: To assess whether human muscle, adipose, and plasma endocannabinoids correlate with EE. Design: Muscle, adipose, and plasma AEA, 2-AG, and OEA concentrations were measured via liquid chromatography-mass spectrometry. EE was assessed by indirect whole-room calorimetry. Setting: Clinical trial. Participants: Obese/overweight Native Americans of full (n = 35) and at least half (n = 21) Southwestern heritage. Main Outcome Measures: Twenty-four-hour EE, sleeping EE (SLEEP), resting EE (REE), respiratory quotient (RQ), and macronutrient oxidation. Results: In full Natives, muscle AEA concentration correlated with SLEEP (r = -0.65, P = 0.004) and REE (r = -0.53, P = 0.02). Muscle 2-AG was associated with SLEEP (r = -0.75, P = 0.0003). Adipose OEA concentration correlated with RQ (r = -0.47, P = 0.04) and lipid oxidation (r = 0.51, P = 0.03). Plasma OEA concentration was associated with SLEEP (r = -0.52, P = 0.04). After adjustment for major determinants, these lipids explained nearly 20% of the additional variance of the respective measure. Similarly, in Native Americans of at least half Southwestern heritage, investigated lipids correlated with EE measures. Conclusion: Endocannabinoids in metabolically relevant peripheral tissues explained a large part of EE variation and may be involved in regulating EE. Dysregulation of peripheral endocannabinoids may predispose people to metabolic diseases via an effect on EE and lipid oxidation.