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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.

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