Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet.
OBJECTIVE
In mice, endocannabinoids (ECs) modulate insulin release from pancreatic beta-cells and adipokine expression in adipocytes through cannabinoid receptors. Their pancreatic and adipose tissue levels are elevated during hyperglycemia and obesity, but the mechanisms underlying these alterations are not understood.


METHODS
We assessed in mice fed for up to 14 weeks with a standard or high-fat diet (HFD): (i) the expression of cannabinoid receptors and EC biosynthesizing enzymes (N-acyl-phosphatidyl-ethanolamine-selective phospholipase D (NAPE-PLD) and DAGLalpha) and degrading enzymes (fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) in pancreatic and adipose tissue sections by immunohistochemical staining; (ii) the amounts, measured by liquid chromatography-mass spectrometry, of the ECs, 2-AG, and anandamide (AEA).


RESULTS
Although CB(1) receptors and biosynthetic enzymes were found mostly in alpha-cells, degrading enzymes were identified in beta-cells. Following HFD, staining for biosynthetic enzymes in beta-cells and lower staining for FAAH were observed together with an increase of EC pancreatic levels. While we observed no diet-induced change in the intensity of the staining of EC metabolic enzymes in the mesenteric visceral fat, a decrease in EC concentrations was accompanied by lower and higher staining of biosynthesizing enzymes and FAAH, respectively, in the subcutaneous fat. No change in cannabinoid receptor staining was observed following HFD in any of the analyzed tissues.


CONCLUSIONS
We provide unprecedented information on the distribution of EC metabolic enzymes in the pancreas and adipose organ, where their aberrant expression during hyperglycemia and obesity contribute to dysregulated EC levels.
Starowicz
Katarzyna M
KM
Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
Cristino
Luigia
L
Matias
Isabel
I
Capasso
Raffaele
R
Racioppi
Alessandro
A
Izzo
Angelo A
AA
Di Marzo
Vincenzo
V
D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000367:Age Factors; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis / Q000378:metabolism*; D002853:Chromatography, Liquid; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005455:Fluorescent Antibody Technique; D005989:Glycerides / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010739:Phospholipase D / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001786:Blood Glucose; D063385:Cannabinoid Receptor Modulators; D004041:Dietary Fats; D063388:Endocannabinoids; D005989:Glycerides; D008071:Lipoprotein Lipase; D008994:Monoacylglycerol Lipases; D010739:Phospholipase D; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C506062:Napepld protein, mouse; C078814:anandamide