Endocannabinoid Anandamide Mediates the Effect of Skeletal Muscle Sphingomyelins on Human Energy Expenditure.

CONTEXT:

Skeletal muscle endocannabinoids and sphingolipids (particularly, sphingomyelins) are inversely associated with sleeping energy expenditure (SLEEP) in humans. The endocannabinoid system may increase sphingolipid synthesis via cannabinoid receptor-1.

OBJECTIVE:

To investigate in human skeletal muscle whether endocannabinoids are responsible for the effect of sphingomyelins on SLEEP.

DESIGN:

Muscle endocannabinoid (anandamide, AEA; 2-arachidonoylglycerol, 2-AG), endocannabinoid congeners (oleoylethanolamide, OEA; palmitoylethanolamide, PEA) and sphingomyelin content were measured using liquid chromatography/mass spectrometry. SLEEP was assessed in a whole-room indirect calorimeter. Mediation analyses tested whether the inverse associations between sphingomyelins and SLEEP depended on endocannabinoids and endocannabinoid-related OEA and PEA.

SETTING:

Inpatient study.

PARTICIPANTS:

Fifty-three overweight Native Americans.

MAIN OUTCOME MEASURE:

SLEEP.

RESULTS:

AEA (r = 0.45, P = 0.001), 2-AG (r = 0.47, P = 0.0004), OEA (r = 0.27, P = 0.05) and PEA (r = 0.53, P < 0.0001) concentrations were associated with the total sphingomyelin content. AEA, OEA, and PEA correlated with specific sphingomyelins (SM18:1/23:0, SM18:1/23:1, and SM18:1/26:1) previously reported to be determinants of SLEEP in Native Americans (all r > 0.31, all P < 0.03). Up to 1/2 of the negative effect of these specific sphingomyelins on SLEEP was accounted by AEA (all P < 0.04), rendering the direct effect by sphingomyelin per se on SLEEP negligible (P > 0.05).

CONCLUSIONS:

In skeletal muscle, AEA is responsible for the sphingomyelin effect on SLEEP, indicating that endocannabinoids and sphingomyelins may jointly reduce human whole-body energy metabolism.