Non-endocannabinoid N-acylethanolamines and 2-monoacylglycerols in the intestine

Abstract

This review focuses on recent findings of the physiological and pharmacological role of non-endocannabinoid N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs) in the intestine and their involvement in the gut-brain signalling. Dietary fat suppresses food intake, and much research concerns the known gut peptides, for example, glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK). NAEs and 2-MAGs represent another class of local gut signals most probably involved in the regulation of food intake. We discuss the putative biosynthetic pathways and targets of NAEs in the intestine as well as their anorectic role and changes in intestinal levels depending on the dietary status. NAEs can activate the transcription factor PPARα, but studies to evaluate the role of endogenous NAEs are generally lacking. Finally, we review the role of diet-derived 2-MAGs in the secretion of anorectic gut peptides via activation of GPR119. Both PPARα and GPR119 have potential as pharmacological targets for the treatment of obesity and the former for treatment of intestinal inflammation. LINKED ARTICLES: This article is part of a themed section on 8^th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Figure 1

Pathways of N‐acetylethanolamine (NAE) formation. NAPE is considered to be the precursor for the formation of NAE. However, at least four pathways can lead to NAE formation. Pathway one is via the enzyme NAPE‐PLD. Pathway two is via the enzymes α,β‐hydrolase domain‐4 (ABHD4) and glycerophosphodiesterase (GDE)1/GDE4, whereby an intermediate GP‐NAE (glycerophospho‐NAE) is formed. Pathway three is via the enzymes ABHD4/sPLA2 and GDE4/GDE7 whereby an intermediate lysoNAPE (lyso‐N‐acyl‐phosphatidylethanolamine) is formed. Pathway four is via the enzymes PLC and a phosphatase, whereby an intermediate NAE phosphate (phospho‐N‐acylethanolamine) is formed. It is not known which pathway is responsible for NAE formation in the small intestine, but mice deficient in NAPE‐PLD do not show changes in intestinal levels of NAPE or NAE.

Figure 2

Endogenous N‐oleoylethanolamine (OEA) may signal dietary status to the brain. Levels of OEA and other anorectic NAEs in the upper small intestine change depend on the dietary status. OEA is a potent activator of PPARα and is suggested to act via the vagus to stimulate dopamine release and reduce food intake and fat desire. Controversial evidence exists with regard to the involvement of the vagus (therefore dashed arrow) mediating the anorectic effects of exogenous OEA, and evidence for the same effect of endogenous OEA is weak. Long‐term feeding of a high‐fat diet (HFD) lowers the levels of OEA in the upper small intestine, and this may explain the increase in energy intake and development of obesity in rodents. Fasting and refeeding change the levels of OEA in opposite ways, which supports a physiological role of OEA in the regulation of food intake. The location of PPARα and the connecting pathway between the receptor and the brain are not completely understood (therefore a question mark).

Figure 3

Pathways of 2‐monoacylglycerol (2‐MAG) formation. 2‐MAG can be formed from both triacylglycerol and phospholipids. In the lumen of the small intestine, in the vasculature and in the adipocytes, TAG (triacylglycerol) can be converted to 2‐MAG by pancreatic lipase, by LPL (lipoprotein lipase), and by the combined action of ATGL/LIPE (adipose‐triglyceride lipase/hormone‐sensitive lipase E) respectively. 2‐MAGs as the well‐known 2‐archidonoylglycerol can be formed via the enzymes PLC/diacylglycerol lipase (DAGL) in many cells. Other pathways from phospholipids may also exist within the cells. FFAs, free fatty acids.

Figure 4

2‐monoacylglycerol (2‐MAG) activates GPR119 and is suggested to be the major stimulator of GLP‐1 release in the intestine after fat intake. Triacylglycerol (TAG) is digested by the lipases to 2‐MAG and free fatty acids (FFAs, not shown) in the gut lumen. Enteroendocrine cells (green) sense 2‐MAG and FFAs through different receptors. GPR119 is one of the fat sensing receptors expressed on the surface of the enteroendocrine cells, and 2‐MAG is an agonist. Activation of GPR119 is known to stimulate the secretion of the hormones GLP‐1, PYY and neurotensin. These are signalling peptides that initially diffuse in the lamina propria (yellow) having various functions in other organs. Different signalling pathways from the gut to other organs have been suggested for these hormones; the vagal and the endocrine via the vasculature are shown here. GPR119 is depicted on both the basolateral and apical membranes of the enteroendocrine cells, as its actual position is yet to be determined.