Protective Role of Flavonoids Against Colonic Motor Dysfunctions Associated with High Fat Diet-Induced Obesity

Introduction. Obesity is a chronic disorder characterized by low-grade systemic inflammation and several comorbidities, including alterations of gastrointestinal (GI) motility. Recent reports suggested the beneficial effects of flavonoids (anti-inflammatory and antioxidant natural compounds) in the prevention of some comorbidities associated with obesity. However, there is a lack of data on the putative effect of this compounds on enteric functional disorders associated with obesity. This study examined the effect of dietary supplementation with luteolin, apigenin and naringenin on colonic inflammatory and motor abnormalities in a mouse model of diet-induced obesity. Methods. C57BL/6 mice (n=5/group) were fed with standard diet (SD, 18% calories from fat) or a high-fat diet (HFD, 60% calories from fat). Subgroups of SD or HFD mice were treated with luteolin (10 mg/Kg/die), apigenin (10 mg/Kg/die) and naringenin (10 mg/Kg/die). After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, triglycerides and glucose levels were evaluated. Malondialdehyde (MDA, colorimetric assay), IL-1β and IL-6 levels (ELISA assays) were examined also in colonic tissues. Colonic longitudinal muscle strips (LMS) were set up in organ baths with Krebs solution and connected to isometric transducers to record contractions elicited by electrical stimulation (ES, 10 Hz, 0.5 msec, 30 mA). Nω-nitro-L-arginine methylester, alone or in combination with guanethidine, atropine, NK2 and NK3 receptor antagonists, were used to record nitrergic and NK1 receptor-mediated tachykininergic motor responses. Results. When compared with SD mice, HFD animals displayed an increase in body and epididymal fat weight, with alterations of blood metabolic indexes (Table). Colonic tissues from HFD mice showed also an increase in MDA, IL-1β and IL-6 levels versus SD mice (Table). Colonic LMS from HFD mice displayed an enhancement of electrically evoked nitrergic and tachykininergic responses (+48% and +126% vs SD mice, respectively). Luteolin, apigenin and naringenin counteracted the increase in body and epididymal fat weight, as well as the alterations of metabolic indexes in HFD mice (Table). In addition, flavonoid administrations reduced MDA, IL-1β, IL-6 colonic levels in HFD mice (Table). Luteolin, apigenin and naringenin normalized also the enhancement of colonic nitrergic and tachykininergic contractions. Of note, treatment with flavonoids did not induce significant changes in metabolic, inflammatory and functional parameters in SD animals, as compared with untreated mice. Conclusion. Diet supplementation with the flavonoid compounds luteolin, apigenin and naringenin prevented the metabolic alterations of obese animals. Moreover, the flavonoid treatment promoted a decrease in intestinal inflammation with a concomitant normalization of colonic dysmotility associated with obesity. Table 1 Summary of the results SD HFD HFD + luteolin HFD + apigenin HFD + naringenin Body and epididymal fat weight Body weight gain (%) 36±2 74±2.6a 46±2* 20±1.8# 28 ±3.3* Epididymal fat weight (g) 0.3 ± 0.02 1.8 ± 0.1c 0.9 ± 0.08* 0.5 ± 0.03$ 0.6 ± 0.09$ Metabolic indexes Cholesterol (mg/dL) 145 ± 5.4 182 ± 7.7a 146 ± 7.5* 142 ± 5.3* 134 ± 3.2# Triglycerides (mg/dL) 118 ± 2.4 149.5 ± 0.03a 143 ± 8.5 109 ± 6.8* 112 ± 2.8* Glucose (mg/dL) 128 ± 7 166 ± 4.8a 133 ± 6* 120 ± 7.3* 116 ± 8.1* Inflammatory parameters MDA (nmol/mg tissue) 61.6 ± 1.6 89.9 ± 1.1c 73.3 ± 2.9* 69.2 ± 3.3* 56.4 ± 6.1# IL-1β (pg/mL tissue) 3.6 ± 0.04 7.6 ± 0.36c 2.1 ± 0.15# 3.3 ± 0.17# 1.8 ±0.17# IL-6 (pg/mL tissue) 0.08 ± 0.01 0.22 ± 0.5a 0.06 ± 0.1* 0.05 ± 0.1* 0.08 ± 0.12* aP < 0.05, cP < 0.001 versus SD