This initially suggested that undernutrition in early development induced permanent alterations in regulatory pathways during periods of developmental plasticity, ultimately mTOR inhibitor resulting in adult disease.7

We and others have currently shown, unequivocally in animal models, that exposure to maternal obesity and overnutrition predisposes offspring to obesity and metabolic dysfunction in adulthood.8, 9 Programmed metabolic abnormalities arising from prenatal and/or early postnatal under- and overnutrition may then be amplified, in the context of postnatal overnutrition, to cause disruption of the adipoinsular axis as well as development of insulin resistance (IR) to promote hepatosteatosis.5 Indeed, there is some evidence, from studies of obese women, that the fetus may already be insulin resistant toward the end of gestation.10 Hepatosteatosis and IR are considered

to be the initiating factors in the pathophysiological cascade underpinning NAFLD, and the process is likely to be propagated by the adipokines, tumor necrosis factor alpha (TNF-α) and interleukin Selleckchem MK-2206 (IL)-6,2 through generation of reactive oxygen species (ROS).11 The hepatic innate immune system is also implicated through inflammatory cytokines IL-12 and IL-18. In addition, destruction of Kupffer cells (KCs) using clodronate liposomes in a mouse model of NASH has been shown to blunt steatosis,12 and it has been proposed that KC-mediated cytokine production impairs lipid peroxidation and propagates IR, culminating in hepatosteatosis.13 Additionally, natural killer T (NKT) cells, potential mediators of an anti-inflammatory response, are selectively reduced in the ob/ob mouse model.14 The protocol in our earlier study,3 though demonstrating a role for maternal overnutrition in the pathogenesis of NAFLD, employed a cross-fostering strategy to delineate the relative role of the in

utero and suckling periods and therefore lacked some physiological Mirabegron relevance. Indeed, we have subsequently shown that the process of offspring cross-fostering can, of itself, induce modest dysmetabolic changes in offspring.15 Therefore, our aim in the present study was to confirm the involvement of developmental programming in the pathogenesis of NAFLD and interrogate the responsible mechanisms using a pathophysiologically relevant murine model in which offspring of dams fed an obesogenic diet are themselves reared on the same diet. The diet, as reported on previously,3, 16 is a highly palatable, high-fat, high-sugar, energy-dense diet designed to mimic the Western diet associated with increased obesity risk.17 We show that offspring of obese dams weaned onto an obesogenic diet developed a more-robust dysmetabolic and NAFLD phenotype, with induction of fibrosis, compared to offspring of lean dams weaned onto the same obesogenic diet or a standard control diet.