Developmental programming of mitochondrial function and pediatric masld

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Oklahoma Health Sciences Center $158,136 on December 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847, Project Grant F32DK146538).

The award funds research into the developmental programming of mitochondrial function in pediatric metabolic-associated steatotic liver disease (MASLD). The work examines how exposure to maternal western diet consumption and obesity during gestation and lactation alters mitochondrial function in hematopoietic stem and progenitor cells, promoting bone marrow-derived macrophage activation and hepatic inflammation that increases offspring susceptibility to metabolic-associated steatohepatitis. The research aims to characterize mechanisms by which mitochondrial dysfunction in early life contributes to long-term inflammation and liver fibrosis in juvenile populations, with MASLD affecting up to 40 percent of children with obesity.

Performance occurs in Oklahoma City, Oklahoma. The period of performance extends from December 1, 2026, through May 31, 2029. The assistance type is a Project Grant.

Abstract

Metabolic-associated steatotic liver disease (masld) is the most prevalent chronic liver disease affecting adults and up to 40% of children with obesity. A growing body of evidence supports the role of early life stressors in the etiology of masld. In humans and animal models, exposure to maternal western diet (MWD) consumption and obesity during gestation and lactation increases offspring risk for steatosis and more severe metabolic- associated steatohepatitis (mash). Mash involves the recruitment of bone marrow derived monocytes to the liver, which give rise to macrophages (MΦ) that are unable to resolve inflammation or repair damage, accelerating liver fibrosis. Previous studies show MWD skews bone marrow (BM) derived MΦ (bmdms) toward a proinflammatory phenotype by remodeling fetal hematopoietic stem and progenitor cells (hspcs). Importantly, hspc programming persists long-term, as bmdms from juvenile offspring exposed to MWD in early life are similarly primed for inflammation by an as-yet characterized mechanism that drives inflammation long term and may contribute to ongoing fibrosis in the juvenile liver. Mitochondrial dysfunction, oxidative stress, and inflammation are hallmarks of MΦ trained immunity but crosstalk between these processes due to MWD and their impact on masld are not well understood. Our preliminary data shows that mononuclear cells (mncs) from BM of 3-week-old mice exposed to MWD have decreased oxidative capacity relative to mncs from BM of control offspring from chow-FED dams. Therefore, we hypothesize that MWD alters mitochondrial function in hspcs during critical windows of early development to promote bmdm activation and hepatic inflammation, thereby increasing susceptibility to mash. The overall goal of this project is to understand the mechanisms for how mitochondria are maladaptive to maternal WD during gestation and/or lactation and how specific pathways contribute to the pathogenesis of inflammation through hspc remodeling of bmdms. This fellowship has two aims: 1) determine the impact of MWD exposure during pregnancy and lactation on hspc and bmdm mitochondrial metabolism in mice at weaning and 2) determine the long-term effect of MWD during gestation or lactation on hepatic MΦ populations, MΦ function, and liver fibrosis in adult offspring following WD challenge. Our approach utilizes metabolomics and proteomics, fluorometry, and respirometry to assess mitochondrial physiology and single cell RNA-sequencing to identify unique populations of hepatic MΦ, capacity for liver repair, and fibrosis in livers of adult mice from the same early life MWD exposures. Completion of this work will provide me with training in mouse research, immune cell metabolism, deeper analysis of mitochondrial physiology, bioinformatics, and use of 'omics technologies to use in my next steps in career development. Impact: the work from this fellowship will fill a GAP in our understanding of maternal diet's impact on the pathogenesis of pediatric masld.