Derailment of the endocannabinoid system by high fat diet starts in adipose tissue
Derailment of the endocannabinoid system by high fat diet starts in adipose tissue
Eline N. Kuipers1#, Vasudev Kantae2#, Boukje C. Eveleens Maarse1, Susan M. van den Berg3, Robin van Eenige1, Kimberly J. Nahon1, Anne Reifel-Miller4, Tamer Coskun4, Menno P.J. de Winther3, Esther Lutgens3,5, Sander Kooijman1,6, Amy C. Harms2, Thomas Hankemeier2, Mario van der Stelt7, Patrick C.N. Rensen1, Mariëtte R. Boon1
1LUMC; 2LACDR; 3AMC; 4Lilly Research Laboratories; 5Ludwig Maximilian’s University; 6University of Oxford; 7Leiden Institute of Chemistry. #Authors contributed equally
Background and aim: The endocannabinoid system (ECS) controls energy balance by regulating both energy intake and energy expenditure. Endocannabinoid levels are elevated in obesity suggesting a potential causal relationship. This study aimed to elucidate the rate of dysregulation of the ECS, and the metabolic organs involved, in diet-induced obesity.
Methods and results: Eight groups of age-matched male C57Bl/6J mice were randomized to receive a chow diet (control) or receive a high fat diet (HFD, 45% of calories derived from fat) ranging from 1 day up to 18 weeks before euthanasia. Plasma levels of the endocannabinoids 2-AG and AEA, and related N-acylethanolamines, were quantified by UPLC-MS/MS and gene expression of components of the ECS was determined in liver, muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) during the course of diet-induced obesity development. HFD feeding gradually increased 2-AG (+132% within 4 weeks, P<0.05), accompanied by upregulated expression of its synthesizing enzymes Daglα and ß in WAT and BAT. HFD also rapidly increased AEA (+81% within 1 week, P<0.01), accompanied by increased expression of its synthesizing enzyme Nape-pld, specifically in BAT. Interestingly, Nape-pld expression in BAT correlated with plasma AEA levels (R2=0.171, β=0.276, P<0.001).
Conclusion: We conclude that a HFD rapidly activates adipose tissue depots to increase the synthesis pathways of endocannabinoids that may aggravate the development of HFD-induced obesity.