Improving Fetal Health Outcomes: Investigating the Impact of Gestational Obesity and NAD⁺ Supplementation on Cardiometabolic Health of Offspring

Abstract

Introduction: Gestational obesity is an increasing concern in North America, associated with adverse pregnancy outcomes and long-term health risks in offspring. Chronic low grade inflammation and placental dysfunction are thought to mediate these effects, partly through depletion of nicotinamide adenine dinucleotide (NAD⁺), a vital coenzyme in cellular metabolism and mitochondrial function.

Objective: This study aimed to investigate how maternal obesity affects offspring cardiometabolic health and to assess whether supplementation with the NAD⁺ precursor nicotinamide riboside (NR) during pregnancy and lactation can mitigate these effects. Methods: Female C57BL/6N mice were fed either a control (CNTRL) or high-fat high-sugar diet for 15 weeks prior to and during pregnancy and lactation. During gestation, mice were either treated with water (CNTRL H₂O = 20, HFHS H₂O = 7) or NR (400 mg/kg/day: CNTRL NR = 16, HFHS NR = 7). Offspring were weaned onto a standard chow diet and assessed for cardiometabolic outcomes between 12 and 47 weeks of age, including glucose tolerance, fat distribution, organ histology, and lipolysis response.

Results: Offspring from HFHS-exposed dams showed early-onset weight gain, elevated fasted blood glucose (specifically in females), and impaired lipolysis in adipose tissues. No changes were observed in blood pressure through to adulthood. NR supplementation mitigated early weight gain and improved glucose handling in a sex-specific manner but did not rescue lipolytic defects or prevent long-term fat accumulation.

Conclusion: Gestational obesity leads to sex-specific, long-term metabolic impairments in offspring, potentially mediated by NAD⁺ depletion. While NR supplementation during pregnancy provided early metabolic protection, it did not fully prevent the long-term consequences. These findings support the potential of NAD⁺ modulation as a therapeutic strategy but highlight the need for further investigation into timing, dosage, and sex-specific responses.