Derailment of the endocannabinoid system by high fat diet starts in adipose tissue - Nederlandse Vereniging voor Endocrinologie

Derailment of the endocannabinoid system by high fat diet starts in adipose tissue

Eline N. Kuipers^1#, Vasudev Kantae^2#, 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 Lutgens^3,5, Sander Kooijman^1,6, 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.