Glucose intolerance as a consequence of hematopoietic stem cell dysfunction in offspring of obese mice
Year: 2024
Type: article
Abstract: OBJECTIVE: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. METHODS: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. RESULTS: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. CONCLUSIONS: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.
Source: Molecular Metabolism
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,870
Funders: March of Dimes Foundation, Indiana University, Ralph W. and Grace M. Showalter Research Trust Fund, Riley Children's Foundation, Nihon Kohden America, National Institutes of Health, School of Medicine, Indiana University, NIHR BioResource, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4401502757