High-fat diet-induced obesity exacerbates inflammatory bowel disease in genetically susceptible Mdr1a-/- male mice

Abstract

Obesity is a chronic inflammatory disease and a risk factor for disorders such as heart disease, diabetes, and cancer. A high-fat diet (HFD), a risk factor for obesity, has also been associated with inflammatory bowel disease (IBD). A proinflammatory state characterized by systemic and local increases in cytokine and chemokine levels are noted in both obesity and IBD, but it is unclear whether obesity is a risk factor for IBD. To examine any association between obesity and IBD, we chose FVB.129P2- Abcb1a(tm1Bor)N7 (Mdr1a(-/-)) mice, because this strain develops IBD spontaneously with age without a chemical or bacterial "trigger." In addition, its background strain, FVB, has been used for diet-induced obesity studies. Mdr1a(-/-) mice and wild-type (WT) mice were fed a HFD (∼60% calories from fat) or a low-fat diet (LFD; ∼11% calories from fat) for 12 wk. Obesity phenotypes examined included body weight measurements, glucose metabolism changes, and adiposity at termination of the study. IBD was determined by clinical signs, necropsy, and histopathology. We found that compared with those fed the LFD, both the Mdr1a(-/-) and WT mice fed the HFD had greater weight gains and elevated plasma leptin concentrations (P < 0.0001). When all mice were analyzed, weight gain was also associated with inflammation in mesenteric fat (R(2) = 0.5; P < 0.0001) and mesenteric lymph nodes (R(2) = 0.4; P < 0.0001). In contrast, the HFD was not associated with IBD in WT mice, whereas it exacerbated spontaneous IBD in Mdr1a(-/-) mice (P = 0.012; Fisher's exact test). Although a HFD and obesity were not associated with IBD in WT mice, our studies suggest that they are likely risk factors for IBD in a genetically susceptible host, such as Mdr1a(-/-) mice.