High fat diet increases circulating endocannabinoids accompanied by increased synthesis enzymes in adipose tissue

Eline N. Kuipers, Vasudev Kantae, Boukje C. Eveleens Maarse, Susan M. Van Den Berg, Robin Van Eenige, Kimberly J. Nahon, Anne Reifel-Miller, Tamer Coskun, Menno P.J. De Winther, Esther Lutgens, Sander Kooijman, Amy C. Harms, Thomas Hankemeier, Mario Van Der Stelt, Patrick C.N. Rensen, Mariëtte R. Boon

Research output: Contribution to journalArticlepeer-review


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. 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-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, 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 β 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). 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.

Original languageEnglish (US)
Article number1913
JournalFrontiers in Physiology
Issue numberJAN
StatePublished - 2019


  • Brown adipose tissue
  • Diet-induced obesity
  • Endocannabinoids
  • White adipose tissue

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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