Early postnatal overfeeding influence on cardiac composition and metabolism in juvenile mice

Introduction

Shortly after birth, the cardiac metabolism shifts from anaerobic glycolysis as the main energy source to predominantly relying on fatty acid β-oxidation. Concomitantly, cardiomyocytes lose their ability to proliferate to switch towards a hypertrophic growth, but variations in the availability and utilization of metabolic substrates influences this postnatal proliferative window. Postnatal overfeeding (PNOF) induced by litter size reduction in rodents mimics the effects of childhood over nutrition.

Objective

The aim of this study was to investigate postnatal cardiac proliferation and early lipid modifications in PNOF juvenile mice.

Method

C57BL/6 male pups were raised in litters adjusted to either 9 or 3 pups to form normally fed (NF) or postnatally overfed (PNOF) group, respectively. Hearts were collected at 7, 10, and 24 days post-birth (PN7, PN10, and PN24, respectively) for immunostaining of the proliferation marker Ki67. Lipidomic analyses were performed using liquid chromatography coupled with mass spectrometry on cardiac tissue and plasma from PN7 pups, as well as on milk from dams nursing PN7 pups. Finally, cardiomyocyte number was evaluated on Malassez counting chamber in PN7 and PN24 hearts.

Results

PNOF pups exhibited significantly higher body weight and cardiac mass compared to NF controls at all time points. An increase in total fatty acids (FA), including saturated long-chain FA and sphingomyelin, was observed in the milk of PN7 dams. At PN7, while circulating fatty acids remained unchanged, cardiolipin and fatty acid contents were significantly decreased in the hearts of PNOF pups. Lipid peroxidation products including oxysterols, HODE and HETE, were also reduced in both plasma and cardiac tissue. At PN7, cardiomyocyte proliferation rate was significantly reduced and associated with an increase in cardiomyocyte surface. Finally, at both PN7 and PN24, a reduction of cardiomyocyte number per milligram of tissue was observed in PNOF mice.

Conclusion

Shortly after birth, the reduction of litter size induces significant changes in milk lipid composition and, consequently, cardiac and plasma lipid changes in PNOF new-borns. PNOF is also associated with cardiomyocyte proliferation changes and cardiomyocyte hypertrophy. Additional investigations are required to determine whether these lipid and cardiac changes are causally linked and to elucidate the mechanisms underlying their relationship.