Abstract
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.
Highlights
MATERIALS AND METHODSObesity is becoming a global epidemic and the need for development of novel therapeutic interventions is high
We demonstrated that high fat diet (HFD) feeding increases circulating levels of endocannabinoids, with a rapid initial increase in AEA and a more gradual increase in 2-AG, in the course of diet-induced obesity (DIO) development
These changes were accompanied by increased gene expression of the synthesis and degradation enzymes of 2-AG in both white adipose tissue (WAT) and brown adipose tissue (BAT), and with increased expression of the AEA synthesis enzyme Nape-pld in BAT
Summary
Obesity is becoming a global epidemic and the need for development of novel therapeutic interventions is high. The endocannabinoid system (ECS) is regarded as a potential therapeutic target since it regulates energy balance by influencing appetite (Foltin et al, 1988; Jamshidi and Taylor, 2001), intracellular lipolysis and energy expenditure [reviewed in (Cota, 2007; Mazier et al, 2015)]. The ECS consists of cannabinoid receptors, their endogenous ligands, the endocannabinoids, and the enzymes that synthesize and degrade the endocannabinoids. The CB1R is expressed centrally and in peripheral metabolic tissues including white adipose tissue (WAT), brown adipose tissue (BAT), liver, skeletal muscle and the pancreas. The CB2R is mainly expressed in immune cells (Howlett et al, 2002)
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