Serum ALT, as a marker of liver injury, was markedly and significantly raised in OffCon-OD and further increased in OffOb-OD (Fig. 3A). These ALK inhibition increases were paralleled by raised expression of IL-6 and TNF-α messenger RNA (mRNA) (Fig. 3B,C). α-SMA, TGF-β, and collagen were all profoundly up-regulated in OffOb-OD (Fig. 3D-F). Histological assessment of hepatosteatosis revealed greater fat infiltration in OffCon-OD, compared to control, at both 3 (Fig. 4A) and 12 months (Fig. 4B). Previous exposure to maternal obesity (OffOb-OD) exacerbated hepatosteatosis at 3 and 12 months (Fig. 4A,B) which was more advanced at 12 months (Fig.
4B). In parallel, there was, at 12 months, clear evidence of histological liver injury in OffCon-OD, as confirmed by the increased Brunt-Kleiner NAS (Fig. 4D), with more-profound injury in OffOb-OD. There was an independent
effect of maternal and postnatal diet on the NAS. Biochemical evidence of fibrogenic pathway activation was corroborated by clear findings of pericellular fibrosis, Ulixertinib cell line on Masson’s trichrome staining, in OffOb-OD (Fig. 4C,E). We then investigated hepatic nonparenchymal cell fraction. The KC population examined by FACS analyses and corroborated by IHC staining was increased in OffOb-OD, but not in OffCon-OD, compared to OffCon-SC (Fig. 5A,B). Despite the increased numbers, KC phagocytic function was impaired (Fig. 5C) in OffOb-OD, compared to OffCon-SC. In contrast, KC ROS production was significantly increased upon LPS stimulation in OffOb-OD, compared to both OffCon-SC HSP90 and OffCon-OD, with a significant interaction between maternal obesity and postweaning diet (Fig. 5D). Furthermore, hepatic expression of the proinflammatory cytokines, IL-12 and IL-18, were similarly up-regulated
in OffOb-OD, compared to controls. There was an independent main effect of maternal diet on IL-12 expression as well as a significant interaction between maternal obesity and postnatal diet for IL-18 expression (Fig. 6A,B). Interestingly, NKT cell numbers were significantly reduced in OffOb-OD (Fig. 6C,D), and there was a significant interaction between maternal and postweaning diets. A substantial body of literature currently suggests that maternal obesity or a hypercalorific diet may, through perturbation of the intrauterine environment, lead to life-long risk of obesity and related metabolic disorders.7 Animal models in particular have proven invaluable in understanding the mechanisms underlying the persistent effects of maternal obesity on the developing offspring and strongly support the hypothesis of the developmental origins of disease.20, 21 Employing a mouse model of maternal obesity, we have previously demonstrated evidence of offspring hyperphagia, increased adiposity, hypertension, IR, and NAFLD in tandem with reduced hepatic insulin signalling and raised sympathetic tone.