298 - Effects of Maternal obesity on metabolic impairment in the second-generation offspring

Publication Number: 298.4961

Marzieh Nemati, Indiana University School of Medicine, Indianapolis, IN, 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; Kok Lim Kua, Indiana University School of Medicine, Indianapolis, IN, United States

Background: Offspring of mothers with obesity have higher risk for obesity and type 2 diabetes. Using a preclinical model, we found that male first-generation offspring (F1) of obese dams exhibited glucose intolerance, while females were unaffected. Given that both male and female F1 have higher adiposity, this raises critical questions whether these metabolic impairments can be transmitted to the second-generation (F2) and how these offspring respond to an obesogenic diet.

Objective: We aim to test the hypothesis that F2 born to F1 sires or dams exposed to maternal obesity (MatOb) have impaired metabolic responses to an obesogenic diet.

Design/Methods: We mated F1 male (MM) and female (MF) of obese mice to control male (CM) or female (CF) animals. All F1 animals remained on standard chow throughout pregnancy and lactation. We generated three F2 groups: offspring born to CM and CF (CMCF) as control, MM X CF (MMCF), and CM X MF (CMMF). Offspring were weaned to chow until 8 weeks of age, after which they were fed either chow or western diet (WD, TD88137) for 4 weeks (n=3-5/sex/group). Glucose tolerance tests (GTT) and body composition were assessed at the end of experiment.

Results: First, we assessed paternal transmission of metabolic phenotypes. 4 weeks after diet randomization, male MMCF-chow was not different from CMCF-chow. Male MMCF-WD had higher glucose levels compared to CMCF-Chow, CMCF-WD, and MMCF-WD. In females, both CMCF-WD and MMCF-WD had similar increase in glucose levels during GTT compared to CMCF-chow (p < 0.05) and MMCF-chow (p < 0.001). Total body adiposity was significantly elevated in CMCF-WD and MMCF-WD compared to CMCF-chow and MMCF-chow in both sexes. Next, we assessed maternal transmission of metabolic phenotypes. Prior to diet challenge, MMCF F2 offspring had unchanged glucose tolerance. Interesting, both male and female F2 CMMF had decrease response to insulin during insulin tolerance testing (at 45, 60 min p< 0.05). Ongoing assessments of CMMF F2 offspring's response to an obesogenic diet challenge will be completed by December.

Conclusion(s): In conclusion, our study demonstrates that transgenerational metabolic risks transmission of MatOb on F2 offspring, particularly in response to obesogenic diet challenge. The findings underscore the importance of maternal health and dietary influences on the metabolic outcomes of future generations, highlighting a critical area for further research and potential intervention strategies to mitigate the risks associated with MatOb.