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

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.

Murine norovirus increases atherosclerotic lesion size and macrophages in Ldlr(-/-) mice.

Murine norovirus (MNV) is prevalent in rodent facilities in the United States. Because MNV has a tropism for macrophages and dendritic cells, we hypothesized that it may alter phenotypes of murine models of inflammatory diseases, such as obesity and atherosclerosis. We examined whether MNV infection influences phenotypes associated with diet-induced obesity and atherosclerosis by using Ldlr(-/-) mice. Male Ldlr(-/-) mice were maintained on either a diabetogenic or high-fat diet for 16 wk, inoculated with either MNV or vehicle, and monitored for changes in body weight, blood glucose, glucose tolerance, and insulin sensitivity. Influence of MNV on atherosclerosis was analyzed by determining aortic sinus lesion area. Under both dietary regimens, MNV-infected and control mice gained similar amounts of weight and developed similar degrees of insulin resistance. However, MNV infection was associated with significant increases in aortic sinus lesion area and macrophage content in Ldlr(-/-) mice fed a high-fat diet but not those fed a diabetogenic diet. In conclusion, MNV infection exacerbates atherosclerosis in Ldlr(-/-) mice fed a high-fat diet but does not influence obesity- and diabetes-related phenotypes. Increased lesion size was associated with increased macrophages, suggesting that MNV may influence macrophage activation or accumulation in the lesion area.

Effects of murine norovirus infection on a mouse model of diet-induced obesity and insulin resistance.

Murine norovirus (MNV) is prevalent in SPF mouse facilities in the United States, and we currently lack sufficient data to determine whether it should be eliminated. It is generally accepted that the virus does not cause clinical symptoms in immuno-competent mice. However, we previously reported that MNV infection alters the phenotype of a mouse model of bacteria-induced inflammatory bowel disease in part through its effects on dendritic cells. The tropism of MNV toward macrophages and dendritic cells makes MNV a potential intercurrent variable in murine models of macrophage-driven inflammatory diseases, such as obesity, insulin resistance, and atherosclerosis. Therefore, we determined whether MNV infection altered obesity and insulin resistance phenotypes in C57BL/6 mice, a widely used model of diet-induced obesity. We found that MNV did not alter weight gain, food intake, and glucose metabolism in this model, but it did induce subtle changes in lymphoid tissue. Further studies using other models of metabolic diseases are needed to provide additional information on the potential role this 'subclinical' virus might have on disease progression in mouse models of inflammatory diseases.

In vitro and in vivo characterization of retinoid synthesis from beta-carotene.

Retinoids are indispensable for the health of mammals, which cannot synthesize retinoids de novo. Retinoids are derived from dietary provitamin A carotenoids, like beta-carotene, through the actions of beta-carotene-15,15'-monooxygenase (BCMO1). As the substrates for retinoid-metabolizing enzymes are water insoluble, they must be transported intracellularly bound to cellular retinol-binding proteins. Our studies suggest that cellular retinol-binding protein, type I (RBP1) acts as an intracellular sensor of retinoid status that, when present as apo-RBP1, stimulates BCMO1 activity and the conversion of carotenoids to retinoids. Cellular retinol-binding protein, type II (RBP2), which is 56% identical to RBP1 does not influence BCMO1 activity. Studies of mice lacking BCMO1 demonstrate that BCMO1 is responsible for metabolically limiting the amount of intact beta-carotene that can be absorbed by mice from their diet. Our studies provide new insights into the regulation of BCMO1 activity and the physiological role of BCMO1 in living organisms.