Using a physiologically relevant model, we investigated the role

Using a physiologically relevant model, we investigated the role of the innate immune system in liver injury

induced by maternal obesity followed by a postnatal obesogenic diet. Female C57BL/6J mice were fed a standard or obesogenic diet before and throughout pregnancy and during lactation. Female offspring were weaned onto a standard or obesogenic diet at 3 weeks postpartum. Biochemical and histological indicators of dysmetabolism, NAFLD and fibrosis, analysis of profibrotic pathways, liver innate immune cells, and reactive oxygen species (ROS) were investigated at 3, 6, and 12 months. Female offspring exposed to a postweaning obesogenic diet (OffCon-OD) demonstrated evidence of liver injury, which was exacerbated by previous exposure to maternal obesity (OffOb-OD), as demonstrated by raised Ku-0059436 alanine aminotransferase, hepatic triglycerides, and hepatic expression of interleukin (IL)-6, tumor necrosis factor alpha, transforming

GSI-IX cost growth factor beta, alpha smooth muscle actin, and collagen (P < 0.01). Histological evidence of hepatosteatosis and a more-robust NAFLD phenotype with hepatic fibrosis was observed at 12 months in OffOb-OD. A role for the innate immune system was indicated by increased Kupffer cell numbers with impaired phagocytic function and raised ROS synthesis (P < 0.01), together with reduced natural killer T cells and raised interleukin (IL)-12 and IL-18. Conclusion: Maternal obesity in the context of a postnatal hypercalorific obesogenic diet aggressively programs offspring NAFLD associated with innate immune dysfunction, resulting in a comprehensive

phenotype that accurately reflects the human disease. (HEPATOLOGY 2013) See Editorial medchemexpress on Page 4 The population prevalence of obesity and nonalcoholic fatty liver disease (NAFLD) are rising worldwide.1 NAFLD, the leading cause of liver dysfunction in developed countries, defines the spectrum from steatosis to cirrhosis and hepatocellular carcinoma,2 with 23%-34% of the U.S. population estimated to have NAFLD and approximately 2.5% the more severe form of the disease, nonalcoholic steatohepatitis (NASH).1 The increasing prevalence of obesity and NAFLD may be partially explained by the increasing availability of inexpensive energy-dense foods, compounded by maternal obesity influencing eventual offspring liver phenotype, as we have previously reported on in a murine model.3 Further studies have corroborated our reports of hepatosteatosis and hepatic inflammation in offspring exposed to maternal obesity or overnutrition.4, 5 This putative deleterious effect of maternal obesity is alarming, given that obesity among women of reproductive age is rising, with current prevalence in the United States approaching 35% in those 20-39 years of age.

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