Inactivation of Group 1B Phospholipase A2 Enhances Disease Recovery and Reduces Experimental Colitis in Mice.

Phospholipase A2 (PLA2) enzymes influence inflammatory bowel disease in both positive and negative manners depending on the type of PLA2 that is expressed. This study explored the influence of the abundantly expressed Group 1B PLA2 (PLA2G1B) on ulcerative colitis. Wild-type C57BL/6J mice and Pla2g1b-/- mice were treated with dextran sulfate sodium (DSS) for 5 days to induce epithelial injury, followed by another 5 days without DSS for recovery. The Pla2g1b-/- mice displayed significantly less body weight loss, colitis pathology, and disease activity indexes compared to the wild-type mice. The differences in colitis were not due to differences in the colonic lysophospholipid levels, but higher numbers of stem and progenitor cells were found in the intestines of Pla2g1b-/- mice compared to the wild-type mice. The DSS-treated Pla2g1b-/- mice also showed higher expressions of genes that are responsible for epithelial repair and lower expressions of proinflammatory cytokine genes in the colon, as well as reduced inflammatory cytokine levels in the plasma. In vitro experiments revealed the PLA2G1B stimulation of inflammatory cytokine expression by myeloid cells. PLA2G1B inactivation protects against DSS-induced colitis in mice by increasing the intestinal stem cell reservoir for epithelial repair and reducing myeloid cell inflammation in the diseased colon. Thus, PLA2G1B may be a target for colitis management.

Different sensitivity to diet-induced hyperinsulinemia and hyperglycemia between mice with global or bone marrow-specific apoE receptor-2 deficiency.

This study explored the role of apoE receptor-2 (apoER2), a unique member of the LDL receptor family proteins with a restricted tissue expression profile, in modulating diet-induced obesity and diabetes. Unlike wild-type mice and humans in which chronic feeding of a high-fat Western-type diet leads to obesity and the prediabetic state of hyperinsulinemia before hyperglycemia onset, the Lrp8-/- mice with global apoER2 deficiency displayed lower body weight and adiposity, slower development of hyperinsulinemia, but the accelerated onset of hyperglycemia. Despite their lower adiposity, adipose tissues in Western diet-fed Lrp8-/- mice were more inflamed compared with wild-type mice. Additional experiments revealed that the hyperglycemia observed in Western diet-fed Lrp8-/- mice was due to impaired glucose-induced insulin secretion, ultimately leading to hyperglycemia, adipocyte dysfunction, and inflammation upon chronic feeding of the Western diet. Interestingly, bone marrow-specific apoER2-deficient mice were not defective in insulin secretion, exhibiting increased adiposity and hyperinsulinemia compared with wild-type mice. Analysis of bone marrow-derived macrophages revealed that apoER2 deficiency impeded inflammation resolution with lower secretion of IFN-ß and IL-10 in response to LPS stimulation of IL-4 primed cells. The apoER2-deficient macrophages also showed an increased level of disabled-2 (Dab2) as well as increased cell surface TLR4, suggesting that apoER2 participates in Dab2 regulation of TLR4 signaling. Taken together, these results showed that apoER2 deficiency in macrophages sustains diet-induced tissue inflammation and accelerates obesity and diabetes onset while apoER2 deficiency in other cell types contributes to hyperglycemia and inflammation via defective insulin secretion.

MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse.

Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intestinal metabolism are related to metabolic outcomes has yet to be established. The lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (Mogat2; MGAT2) plays a crucial role in the assimilation of dietary fat in the intestine and in regulation of adiposity stores as well. Given the phenotypic similarities between VSG-operated and MGAT2-deficient animals, we reasoned that this enzyme could also have a key role in mediating the metabolic benefits of VSG. However, VSG reduced body weight and fat mass and improved glucose metabolism similarly in whole body MGAT2-deficient (Mogat2(-/-)) mice and wild-type littermates. Furthermore, along with an increase in energy expenditure, surgically naive Mogat2(-/-) mice had altered macronutrient preference, shifting preference away from fat and toward carbohydrates, and increased locomotor activity. Collectively, these data suggest that the beneficial effects of VSG on body weight and glucose metabolism are independent of MGAT2 activity and rather that they are separate from the effects of MGAT2 deficiency. Because MGAT2 inhibitors are proposed as a pharmacotherapeutic option for obesity, our data suggest that, in addition to increasing energy expenditure, shifting macronutrient preference away from fat could be another important mechanism by which these compounds could contribute to weight loss.

Perinatal exposure to bisphenol-a and the development of metabolic syndrome in CD-1 mice.

Bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of plastic food and beverage containers, leading to ubiquitous low-dose human exposure. It has been suggested that exposure to even low doses of BPA during development may be associated with increased susceptibility to obesity and diabetes later in life. Despite growing public concern, the existing empirical data are equivocal, prompting The Endocrine Society, the National Institute of Environmental Health Sciences, and others to call for further research. In this study, we tested the hypothesis that perinatal exposure to an ecologically relevant dose of BPA (1 part per billion via the diet) results in increased susceptibility to high-fat diet-induced obesity and glucose intolerance in adult CD-1 mice. The data did not support this hypothesis. In agreement with previous reports, we find that weanling mice exposed to BPA during gestation and lactation are heavier compared with control mice. We also find that BPA mice are longer than controls at 4 wk of age, but these differences are no longer apparent when the mice reach adulthood, even when tested on a high-fat diet. We conclude that this larger size-for-age represents a faster rate of growth early in development rather than an obese, diabetic phenotype in adulthood.