Maternal obesity perturbs liver development and zonation in progeny

Maternal obesity is an independent risk factor for pediatric fatty liver disease and type 2 diabetes mellitus. Globally, 10% of children are predicted to have metabolic associated fatty liver disease (MAFLD), rising to 36% in obese children. MALFD encompasses a spectrum of liver disorders characterized by progressive steatosis and inflammation and more serve forms such as metabolic associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately liver failure. The etiology of adult and pediatric MAFLD and MASH are distinct yet the mechanisms that drive these differences are not well understood and increasing evidence suggests the onset of pediatric MAFLD may have fetal origins. MAFLD/MASH manifests as periportal injury in pediatric patients whereas it develops in the pericentral region in adults. The stratification of metabolic pathways such as lipid metabolism, fatty acid oxidation, gluconeogenesis and bile acid production into district metabolic zones; periportal, mid-lobule and pericentral, is critical for normal hepatic function and metabolic plasticity. While the liver architecture is fully developed in-utero, the maturation of the liver zones occurs postnatally, and the effect of maternal obesity on hepatic zonal development and thus metabolic function has not been investigated. We hypothesize that maternal obesity, in utero and/or during lactation leads to dysregulation of liver zonation and its respective metabolic functions, leading to periportal liver injury and pediatric MASH. Here, we use a mouse model of maternal obesity in which dams are fed either chow or high fat diet (HFD) (11 and 45% fat w/v, respectively) for 10 weeks before and during gestation and subsequently the pups are cross fostered with a lactating dam fed the opposite diet to dissect the effects of maternal obesity in utero and/or during lactation. Maternal obesity during lactation, irrespective of gestational diet, significantly increased both liver and body weight (1.5-fold) and hepatic steatosis (Oil Red O staining) of pups at p30. Maternal obesity during gestation, followed by lactation to a lean dam, did not result in weight gain in p30 pups, nevertheless immunostaining of liver sections with zonal markers revealed a 20% increase in the periportal region (E-cadherin+), with a corresponding 20% = decrease in the mid-lobule region (E-cadherin and Glutamine Synthetase negative) demonstrating a deficit in hepatic zonation. Furthermore, hepatic stellate cell (HSC) number (GFAP+ staining) increased in response to maternal obesity during gestation, indicative of elevated inflammation/injury. Our preliminary spatial metabolomics data also revealed that the zonally discrete metabolite distribution patterns observed in control liver were lost in the liver from p30 offspring of obese dams. To summarize, maternal obesity increases hepatic steatosis, inflammation and dysregulates the zonal stratification of metabolic pathways. Hepatic zonation is controlled by the release of Wnt, Jagged and Hedgehog ligands from the non-parenchymal liver cells, such as Kupffer cells, HSCs and sinusoidal endothelial cells. Our future experiments will employ spatial single cell transcriptomics and predictive computational modeling to establish how maternal obesity affects the liver microenvironment, cell to cell communication and the development of liver zonation. These studies will help us delineate the metabolic and signaling pathways that are dysregulated by maternal obesity that precipitate long term metabolic dysfunction. Funding sources: This work was supported by NIH grant 1R01DK139244 (PJB) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.