High Fat Diet Increases Circulating Endocannabinoids Accompanied by Increased Synthesis Enzymes in Adipose Tissue

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.

Hypothalamic endocannabinoids inversely correlate with the development of diet-induced obesity in male and female mice

“…Interestingly, these results negatively correlated with those concentrations in the hypothalamus. In line with these evidences, Kuipers et al (41) recently demonstrated that there is a link between eCB metabolism in adipose tissues and plasmatic eCBs during DIO development. They showed that long-term HFD feeding increases circulating eCBs, accompanied by increased synthesis enzymes in adipose tissue (particularly BAT) of DIO mice (41).…”

“…In line with these evidences, Kuipers et al (41) recently demonstrated that there is a link between eCB metabolism in adipose tissues and plasmatic eCBs during DIO development. They showed that long-term HFD feeding increases circulating eCBs, accompanied by increased synthesis enzymes in adipose tissue (particularly BAT) of DIO mice (41). The authors also suggest that adipose tissues are likely important organs that release 2-AG and AEA levels in HFD-induced obesity (41).…”

“…They showed that long-term HFD feeding increases circulating eCBs, accompanied by increased synthesis enzymes in adipose tissue (particularly BAT) of DIO mice (41). The authors also suggest that adipose tissues are likely important organs that release 2-AG and AEA levels in HFD-induced obesity (41).…”

Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome

“…In the liver, a high-fat diet increased AEA levels and CB1 signaling, which contributed to the activation of genetic programs that increase fatty acid production [13]. In a very recent study in which circulating eCBome levels were tracked over time in mice on a high-fat diet, AEA, PEA, and N -docosahexanoylethanolamine (DHEA) levels increased rapidly over the course of a week, while SEA and 2-AG increases became significant only after 4 weeks and, finally, OEA increased after 10 weeks [44]. While gene expression changes in eCBome enzymes were observed in muscle and liver tissues, they were transient; however, the expression of the 2-AG anabolic enzyme DAGLβ was constantly increased in white and brown adipose tissue (BAT) from 4 weeks, while the NAE anabolic enzyme NAPE-PLD was constantly increased only in the BAT from 3 days on [44].…”

Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis

“…ghrelin, leptin, GLP-1, CCK) (Gribble and Reimann, 2019), peripheral endocannabinoids (eCBs) may be fundamental players in the regulation of feeding and metabolic efficiency (Argueta and DiPatrizio, 2017; Capasso et al, 2018; DiPatrizio et al, 2013; Gómez et al, 2002; Izzo et al, 2009). Indeed, eating disorders-associated alterations in peripheral eCBs have been reported in obese and BE patients (Monteleone et al, 2016, 2017, 2005; Quarta et al, 2011) as well as in diet-induced obese rodents (Argueta and DiPatrizio, 2017; Kuipers et al, 2018). However, whether and how peripheral eCBs play a permissive role in both guiding reward-based feeding behaviors and buffering the allostatic regulation of energy balance remain still unexplored.…”