48 - Sex-differences in glucose metabolism regulated by hematopoietic stem and progenitor cells in offspring of obese mice

Saturday, April 29, 2023

3:30 PM – 6:00 PM ET

Poster Number: 48
Publication Number: 48.253

Merve Denizli, Indiana University School of Medicine, Indianapolis, IN, United States; James Ropa, Indiana University School of Medicine, Indianapolis, IN, United States; Lindsay Beasley, Indiana University School of Medicine, Indianapolis, IN, United States; Laura Haneline, 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

Presenting Author(s)

Merve Denizli, MD (she/her/hers)

Neonatal-Perinatal Fellow
Indiana University School of Medicine
Indianapolis, Indiana, United States

Background: Offspring of mothers with obesity are at higher risk of developing type 2 diabetes due to the combination of insulin resistance, β-cell dysfunction, and increased inflammation. The role of hematopoietic stem and progenitor cells (HSPC) as the origin of altered immune profile and their potential role as a regulator of β-cell health has been proposed in type 1 diabetes pathogenesis. However, the role of HSPC in the context of offspring of mothers with obesity, particularly in regulating offspring metabolic health, has not been studied. Compared to same-sex controls, we reported that male pups born to diet-induced obese dams (MatOb) developed glucose intolerance while female MatOb pups did not.

Objective: We hypothesize the role of HSPC in regulating insulin sensitivity and β-cell health, resulting in sex-differences in glucose intolerance of MatOb offspring.

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+ cells) were 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, pancreatic β-, and α-cell area were assessed (all groups have n of 4-8/sex/group, * indicates p< 0.05).

Results:

16 weeks after the primary transplant, there were no differences detected in body weight and adiposity. Compared to sex-matched controls, we found that recipients 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 β-cell area (42±11% lower than Con*), supporting the presence of impaired glucose metabolism due to a combination of insulin resistance and lower β-cell mass.

Conclusion(s):

Our data showed that the observed glucose intolerance in recipient mice recapitulated the sex-differences in donor glucose intolerance. Together, these data support the novel role of HSPC in regulating glucose metabolism. The molecular mechanisms by which altered HSPC function leads to altered glucose metabolism warrant further investigation.