Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion

• Published in: American journal of physiology: endocrinology and metabolism Vol. 315; no. 4; pp. E489 - E495
• Main Authors: Little, Tanya J, Cvijanovic, Nada, DiPatrizio, Nicholas V, Argueta, Donovan A, Rayner, Christopher K, Feinle-Bisset, Christine, Young, Richard L
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2018
• Series: Endocannabinoids and Cannabinoid Receptors as Regulators of Endocrine Functions and Tissue Metabolism
• Subjects: Adult; Alkaline Phosphatase - genetics; Anandamide; Arachidonic Acids - blood; Biomass; Biopsy; Body mass; Body weight; Cannabinoids; Diet; Dietary Fats - metabolism; Digestive system; Duodenum - metabolism; Endocannabinoids - blood; Female; Gastric Inhibitory Polypeptide - blood; Gene Expression; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - blood; Glycerides - blood; Glycerol; GPI-Linked Proteins - genetics; High fat diet; High-performance liquid chromatography; Humans; Incretins - metabolism; Inflammation; Inflammation - immunology; Intestine; Lipids; Liquid chromatography; Male; Markers; Mass spectrometry; Mass spectroscopy; Microbiomes; Obesity; Obesity - blood; Obesity - immunology; Obesity - metabolism; Occludin - genetics; Oleic acid; Oleic Acids - blood; Overweight; Overweight - blood; Overweight - immunology; Overweight - metabolism; Permeability; Polymerase chain reaction; Polyunsaturated Alkamides - blood; Rodents; Satiety; Secretion; Thinness - blood; Thinness - immunology; Thinness - metabolism; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; Zonula occludens-1 protein; Zonula Occludens-1 Protein - genetics; inflammation tight-junction proteins; n-acylethanolamines; anandamide; intestinal fat sensors; 2-arachidonylglycerol
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00355.2017

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.