744 - The Protective Role of IL-10 on Hematopoietic Stem and Progenitor Cells in Offspring of Obese Mice: Implications for Glucose Intolerance

Publication Number: 744.6815

Merve Denizli, Oklahoma Childrens Hospital at OU Health, Oklahoma City, OK, United States; Kelli A. DeVanna, Indiana University School of Medicine, Indianapolis, IN, United States; Taylor J. Spice, Indiana University School of Medicine, Noblesville, IN, United States; Marzieh Nemati, Indiana University School of Medicine, Indianapolis, IN, United States; Lindsay Wathen, Indiana University School of Medicine, Indianapolis, IN, United States; Maegan Capitano, Indiana University School of Medicine, Indianapolis, IN, United States; Kok Lim Kua, Indiana University School of Medicine, Indianapolis, IN, United States

Background: Maternal obesity impacts one in three pregnancies in the United States, increasing the risks of developing several chronic illnesses in offspring, including leukemia, allergy/atopy, obesity, and type 2 diabetes. These diseases share characteristics of metabolic dysfunction, immune dysregulation, and altered hematopoiesis, linking the role of maternal obesity to altered hematopoietic stem and progenitor cell (HSPC) function. We recently reported that maternal obesity disproportionately impacted HSPC function in the male offspring exposed to maternal obesity compared to the same sex control, while female offspring of obese mice were unaffected. We further demonstrated the novel role of HSPCs in regulating sex-differences in glucose tolerance in offspring of obese mice and this is potentially regulated by anti-inflammatory cytokine interleukin-10 (IL-10).

Objective: The goal of this study is to test the hypothesis that IL-10 has a protective effect on HSPC and HPC, and improvement in HSPC function would rescue glucose intolerance.

Design/Methods: We assessed the impact of in-vivo recombinant IL-10 treatment in male offspring of obese mice from postnatal day 14 (P14) to 21 (P21) on offspring HSPC function. We also treated female offspring of obese mice with IgG control or IL-10 receptor blocker (IL-10rb) from P14-P21. HSPCs were isolated for competitive repopulation assay to assess function of HSPCs, and glucose tolerance testing was performed in recipients at the end of end of experiment. N=4-5/sex-group.

Results: We found that HSPCs isolated from male pups born to obese dams had lower % chimerism 10 weeks post-transplant compared to HSPCs from same-sex Con, while HSPCs from male pups of obese dams treated with IL-10 had improved chimerism, indicating that treatment with IL-10 rescued HSPCs function in male offspring of obese mice. We also found that recipients of HSPCs from male pups of obese dams treated with PBS had decreased glucose tolerance, while recipients of HSPCs from pups of obese dams treated with IL-10 had unchanged glucose tolerance compared to same-sex control. In contrast, we found that HSPCs from female offspring of obese mice received IgG had higher chimerism, this increase was ablated in HSPCs from female MatOb mice received IL-10rb.

Conclusion(s): Taken together, our results show that IL-10 as a central regulator of sex-differences in response to maternal obesity exposure, and may have a protective effect on HSPCs in-vivo which in turn could improve glucose tolerance.