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Research Project: Impact of Maternal Influence and Early Dietary Factors on Child Growth, Development, and Metabolic Health

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Title: Neonatal diet impacts liver mitochondrial bioenergetics in piglets fed formula or human milk

item CARVALHO, EUGENIA - Arkansas Children'S Nutrition Research Center (ACNC)
item Ferruzzi, Mario
item BORSHEIM, ELISABET - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - University Arkansas For Medical Sciences (UAMS)
item ONO-MOORE, KIKUMI - University Arkansas For Medical Sciences (UAMS)
item COTTER, MATTHEW - Arkansas Children'S Nutrition Research Center (ACNC)
item BOWLIN, ANNE - University Arkansas For Medical Sciences (UAMS)
item YERUVA, LAXMI - University Arkansas For Medical Sciences (UAMS)

Submitted to: BMC Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2020
Publication Date: 4/15/2020
Publication URL:
Citation: Carvalho, E., Adams, S.H., Borsheim, E., Blackburn, M.L., Ono-Moore, K.D., Cotter, M., Bowlin, A.K., Yeruva, L. 2020. Neonatal diet impacts liver mitochondrial bioenergetics in piglets fed formula or human milk. Biomed Central (BMC) Nutrition. 6:13.

Interpretive Summary: The type of neonatal diet (e.g., formula vs. breastmilk) has been shown to impact many physiological systems during infancy and beyond. However, little is known about how feeding type as a baby can impact how the body converts food energy ("bioenergetics") in specialized cellular structures called mitochondria. Human milk (HM) or milk formula (MF) feeding was tested for their effects on mitochondrial bioenergetics in a piglet animal model that shares many aspects of the gastrointestinal tract and liver with human babies. The purpose of this study was to determine the characteristics of gut and liver mitochondrial bioenergetics (tissue oxygen consumption, a.k.a. tissue respiration) in neonatal piglets fed with HM or MF through day 21. No significant diet-associated differences were observed in ileum tissue for all parameters tested: respiration in the presence of fuel substrates or substrates in combination with inhibitors that allow for detection of "leak" or inefficiencies in respiration. In liver, MF led to higher substrate (succinate, pyruvate, malate, glutamate) plus ADP-driven respiration. The data suggest higher mitochondrial respiration can be programmed by early-life intake of certain formulas or specific milk components. Furthermore, since there were no increases in mitochondrial numbers in MF-fed piglets, there seems to be higher intrinsic respiration per mitochondrion, in MF conditions. Overall, the studies highlight a very important principle that was not previously appreciated: infant diet type has the potential to regulate the body's bioenergetics systems. More research is required to determine if these outcomes also take place in human babies. If so, then it will be important to consider how formulas versus breastfeeding can influence the systems that regulate conversion of energy from food to fuel the body's functions in the gut and in other tissues.

Technical Abstract: Neonatal diet impacts many physiological systems and can modify risk for developing metabolic disease and obesity later in life. Less well studied is the effect of postnatal diet (e.g., comparing human milk (HM) or milk formula (MF) feeding) on mitochondrial bioenergetics. Such effects may be most profound in splanchnic tissues that would have early exposure to diet-associated or gut microbe-derived factors. To address this question, we measured ileal and liver mitochondrial bioenergetics phenotypes in piglets fed with HM or MF from day 2 to day 21. Ileal and liver tissue were processed for mitochondrial respiration (substrate only, substrate + ADP, and proton "leak" postoligomycin; measured by Oroboros methods), mitochondrial DNA (mtDNA) and metabolically-relevant gene expression analyses. No differences between the diet groups were observed in mitochondrial bioenergetics indices in ileal tissue. In contrast, ADP-dependent liver Complex I-linked OXPHOS capacity and Complex I+II-linked OXPHOS capacity were significantly higher in MF animals relative to HM fed piglets. Interestingly, p53, Trap1, and PparB transcript abundances were higher in MF-fed relative to HM-fed piglets in the liver. Mitochondrial DNA copy numbers (normalized to nuclear DNA) were similar within-tissue regardless of postnatal diet, and were ~2-3 times higher in liver vs. ileal tissue. While mechanisms remain to be identified, the data indicate that neonatal diet can significantly impact liver mitochondrial bioenergetics phenotypes, even in the absence of a change in mtDNA abundance. Since permeabilized liver mitochondrial respiration was increased in MF piglets only in the presence of ADP, it suggests that formula feeding led to a higher ATP turnover. Specific mechanisms and signals involved with neonatal diet-associated differences in liver bioenergetics remain to be elucidated.