Functional alteration of gastrointestinal tract in a mouse model of diet induced-obesit

Background and Aim: Obesity, beyond an excessive fat accumulation, induces the onset and progression of chronic disorders such as cardiovascular disease, type 2 diabetes and cancer (1). Obesity is also associated with gastrointestinal dysfunctions, including altered gastric emptying, intestinal dysmotility and constipation (2). The aim of the study is to evaluate the small intestine contractility and gut motility in a mouse model of diet-induced obesity (DIO). Methods: C57BL/6 female mice (4-5 weeks of age) were fed with standard diet (SD, 10% of energy from fat) or high fat diet (HFD, 60% of energy from fat) for 8 weeks. Body weight, fecal pellet frequency and stool water content were evaluated the day before sacrifice. Gastrointestinal transit was assessed 30 minutes after intragastric administration of nonabsorbable fluorescein isothiocyanate labeled dextran (FITC-dextran 70 KDa). Isolated ileum segments were isometrically mounted in organ baths containing Krebs solution and changes in muscle tension were recorded following addition of either carbachol (0.01-100 μM), KCl (60 mM) and after electric field stimulation (EFS, 1-40 Hz). The inhibitory contractile response was evaluated by performing the EFS at 10 Hz in non-adrenergic non-cholinergic (NANC) conditions (1 μM atropine, 1 μM guanethidine) in the absence or presence of 10 μM 1400W or 100 μM L-NAME. Results: HFD-mice (n=35) displayed an increase of body weight after 8 weeks on diet (21.28 ± 0.46 g) compared to control SD mice (n=19, 19.26 ± 0.33 g, p<0.05) and a 50% reduction in fecal pellet extruded in 1-hour period and in stool water content. Gastrointestinal transit showed a significantly reduction in HFD-mice. A slight downward shift of the concentration-response curve to CCh occurred in HFD-mice, and KCl-mediated contractions significantly decreased (-33%) compared with SD group. Neuronal cholinergic responses to EFS were significantly reduced in ileum segments of HFD mice (-57%). In NANC conditions, EFS at 10 Hz caused a slight increase (not significant) in relaxation in HFD mice. Pretreatment with 1400W, a selective inhibitor of iNOS, did not affect 10 Hz EFS-induced relaxation in NANC conditions, whereas addition of the non-selective NOS inhibitor L-NAME blocked EFS-evoked NANC relaxation in SD and HFD mice. Conclusion: HFD-induced obesity determines alterations in small intestine neuromuscular contractility and gut motility, potentially due to impairment of the excitatory pathways responsible in controlling intestinal function.