Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue.
Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R-/-mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R-/-, suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the antilipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test if the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
Tania
T
Muller
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
Laurent
L
Demizieux
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
Stéphanie
S
Troy-Fioramonti
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
Joseph
J
Gresti
Jean-Paul Pais de Barros, Lipidomic Platform, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France; and.
Jean-Paul
JP
Pais de Barros
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
Hélène
H
Berger
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.|Endocrinology, Diabetology Department, University Hospital of Dijon, Dijon, France.
Bruno
B
Vergès
Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France; pascal.degrace@u-bourgogne.fr.
Pascal
P
Degrace
D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D063388:Endocannabinoids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000096:biosynthesis; D006868:Hydrolysis; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D063388:Endocannabinoids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D043884:Receptor, Cannabinoid, CB1
JZL195; cannabinoid receptor 1; endocannabinoid system; insulin resistance; lipolysis