(34) Novel Role of HPSC in Regulating Glucose Metabolism in Offspring of Obese Mice

Merve Denizli, Indiana University School of Medicine, Fishers, IN, United States; James Ropa, Indiana University School of Medicine, United States; Lindsay N. Beasley, Indiana University School of Medicine, United States; Laura Haneline, Indiana University School of Medicine; Riley Children’s Hospital, United States; Maegan Capitano, Indiana University School of Medicine, United States; Kok Lim Kua, Indiana University School of Medicine, United States

Background: Offspring of mothers with obesity are at higher risk of developing type 2 diabetes due to a combination of insulin resistance, increased inflammation, and islet dysfunction. Additionally, these children are at higher risk of other diseases such as neuropsychiatric disorders, allergy/asthma, and leukemia, many of which involves altered immune profiles or hematopoiesis suggesting the role of hematopoietic stem and progenitor cells (HSPC) as the cellular origin. Using a diet-induced maternal obesity model, we previously reported that compared to sex-matched controls, both male pups of obese dams (MatOB) developed glucose intolerance while female MatOb pups did not.

Objectives: We hypothesize the role of HSPC in regulating offspring in-vivo glucose metabolism, where recipients of HSPC isolated from male offspring of obese mice had decreased glucose tolerance.

Design/Methods: Female dams were fed with chow (Con) or western diet (MatOb) for four weeks prior to mating, through pregnancy, and the lactating period. At postnatal day 21 (P21), HSPC (Lin- Sca-1+ cKit+) was flow-sorted from offspring bone marrow (BM) for competitive transplant into same-sex irradiated mice. Body weight, body adiposity, and glucose tolerance test (GTT) were performed on male and female recipients. Fasting insulin and pancreatic beta/alpha cell area were assessed as well. All groups have n of 4-8/sex/group and * indicates p< 0.05.

Results: At 24 weeks after the primary transplant, there were no differences detected in body weight and adiposity. Compared to sex-matched controls, we found that recipients that were transplanted with male MatOb mice HSPC developed glucose intolerance (GTT glucose AUC 15±4% higher than Con*). In contrast, there was no difference in recipients of female Con and female MatOb pups. Recipients of male MatOb pups also demonstrated increased fasting insulin (52±28% higher than Con, p=0.05) and decreased ẞ-cell area (42±11% lower than Con*), supporting the presence of impaired glucose metabolism due to a combination of insulin resistance and lower beta-cell mass.

Conclusion: Together these data support the novel role of HSPC in regulating glucose metabolism. However, the molecular mechanisms underlying the altered HSC function and the relationship to altered glucose metabolism are unknown and warrant further investigation.