Colonic motor dysfunctions in a mouse model of high-fat diet-induced obesity: an involvement of A2B adenosine receptors

Abstract

Adenosine A receptors (AR) regulate several enteric functions. However, their implication in the pathophysiology of intestinal dysmotility associated with high-fat diet (HFD)-induced obesity has not been elucidated. We investigated the expression of AR in mouse colon and their role in the mechanisms underlying the development of enteric dysmotility associated with obesity. Wild-type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD; 18% kcal from fat) for 8 weeks. Colonic AR localization was examined by immunofluorescence. The role of AR in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). In NCD mice, AR were predominantly located in myenteric neurons; in HFD animals, their expression increased throughout the neuromuscular layer. Functionally, the AR antagonist MRS1754 enhanced electrically induced NK-mediated tachykininergic contractions in LMPs from HFD mice, while it was less effective in tissues from NCD mice. The A receptor agonist BAY 60-6583 decreased colonic tachykininergic contractions in LMPs, with higher efficacy in preparations from obese mice. Both AR ligands did not affect contractions elicited by exogenous substance P. Obesity is related with a condition of colonic inflammation, leading to an increase of AR expression. AR, modulating the activity of excitatory tachykininergic nerves, participate to the enteric dysmotility associated with obesity.

Luteolin Prevents Cardiometabolic Alterations and Vascular Dysfunction in Mice With HFD-Induced Obesity

“…Furthermore, among the obesogenic diets, HFD contributes significantly to weight gain, the consequent development of obesity, and related disorders ( Mozaffarian et al, 2011 ). Our results are in keeping with previous observations ( Antonioli et al, 2017 ), confirming that mice fed with HFD for 8 weeks developed a marked increase in body and epididymal fat weight associated with an elevation of total cholesterol, triglycerides, and glucose, thus corroborating further the suitability of this experimental model.…”

The flavonoid compound apigenin prevents colonic inflammation and motor dysfunctions associated with high fat diet-induced obesity

“…Of interest, in the present study signs of this mild inflammatory condition, which was associated with an increased level of oxidative stress, were observed in colonic specimens from HFD mice, as documented by the significant increment of IL-1β, IL-6 and MDA tissue concentrations and eosinophil density. These findings are in line with previous preclinical studies, reporting marked increments of IL-1β, IL-12p40 [ 30 ], IL-6, MDA and eosinophil infiltration [ 18 ] in colon tissues from HFD mice, as well as with clinical observations indicating an increase in IL-1β, IL-6, IL-8, TNF and monocyte chemotactic protein (MCP-1) in colonic mucosal samples from obese patients [ 31 ]. Our data on the expression of let-7f microRNA, which belongs to the highly conserved let-7 family [ 32 ], are consistent with previous findings, showing a decrease in let-7f levels in the colonic mucosa of diet-induced obesity in mice, and an increase in let-7f levels in mice subjective to caloric restriction [ 33 ].…”

“…8-μm-thick slices from full-thickness, formalin-fixed, paraffin-embedded colonic samples were processed to evaluate the morphology of colonic wall by haematoxylin/eosin and immunoperoxidase staining (see below). The severity and extent of inflammatory infiltrations were evaluated on the basis of the percentage of leucocytes per microscopic field and their presence through the colonic wall layers, respectively, as previously described [ 18 ]. The density of eosinophils was estimated within the tunica mucosa/submucosa and expressed as cell number per square millimeter as described in detail previously by Pellegrini and coworkers [ 19 ].…”

Inflammatory Links Between High Fat Diets and Diseases

“…In addition, increased amounts of FFAs present in HFDs may directly act on intestinal cells. Therefore, elevated release of LPS and/or increased FFAs levels led to elevated production of pro-inflammatory cytokines [i.e., interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α] in the gut ( 13 – 17 ). The second step may consist in increased delivery of intestinal LPS, pro-inflammatory cytokines, and FFAs into the systemic circulation and portal circulation, thus leading to a systemic low-grade inflammation ( 15 , 18 ).…”