Iron, ketone bodies, and brain development

Abstract

Iron deficiency is deleterious in early life brain development and a risk for short- and long-term cognitive, motor, and socioemotional impairment.1Georgieff M.K. Iron assessment to protect the developing brain.Am J Clin Nutr. 2017; 106: 1588S-1593SCrossref PubMed Scopus (63) Google Scholar,2Prado E.L. Dewey K.G. Nutrition and brain development in early life.Nutr Rev. 2014; 72: 267-284Crossref PubMed Scopus (418) Google Scholar Parkin et al recently reported that increasing serum ferritin values, up to a level of 17 μg/L, were correlated with higher cognitive function in infants of 1-3 years of age.3Parkin P.C. Koroshegyi C. Mamak E. Borkhoff C.M. Birken C.S. Maguire J.L. et al.TARGet Kids! Collaboration. Association between serum ferritin and cognitive function in early childhood.J Pediatr. 2020; 217: 189-191Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Here, we address another aspect of the role of iron deficiency in brain development in relation to ketone bodies as an energy source for brain metabolism. In the starved state, ketone bodies are synthesized from free fatty acids produced by breakdown of body fat, and cross the blood-brain barrier for use in brain metabolism. Ketone bodies may have neuroprotective effects and a ketogenic diet is used in treatment of neurological diseases such as refractory epilepsy, Parkinson disease, Alzheimer disease, and traumatic brain injury.4Kossoff E. Hartman A. Ketogenic diets: new advances for metabolism-based therapies.Curr Opin Neurol. 2012; 25: 173-178Crossref PubMed Scopus (88) Google Scholar,5Yang H. Shan W. Zhu F. Wu J. Wang Q. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms.Front Neurol. 2019; 10: 585Crossref PubMed Scopus (59) Google Scholar Kuzawa and Blair hypothesized that body fat is a critical brain energy source, especially during infancy and early childhood.6Kuzawa C.W. Blair C. A hypothesis linking the energy demand of the brain to obesity risk.Proc Natl Acad Sci U S A. 2019; 116: 13266-13275Crossref PubMed Scopus (20) Google Scholar In this period, the brain consumes about 40% of daily energy expenditure (20% for adults). Glucose alone cannot supply this energy, and ketone bodies are used. Thus, brain energy expenditure is inversely related to body fat gain (increased body mass index) during early childhood, and thus, decreases the risk of obesity.6Kuzawa C.W. Blair C. A hypothesis linking the energy demand of the brain to obesity risk.Proc Natl Acad Sci U S A. 2019; 116: 13266-13275Crossref PubMed Scopus (20) Google Scholar,7Arisaka O. Ichikawa G. Koyama S. Sairenchi T. Implication of late adiposity rebound.J Pediatr. 2020; 219: 284Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar In an iron-deficient state, ketogenesis is impaired, citrate synthase and succinate dehydrogenase activities are decreased, and production of free fatty acids and ketone bodies is limited.8Bartholmey S.J. Sherman A.R. Impaired ketogenesis in iron-deficient rat pups.J Nutr. 1986; 116: 2180-2189Crossref PubMed Scopus (10) Google Scholar,9Oexle H. Gnaiger E. Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation.Biochim Biophys Acta. 1999; 1413: 99-107Crossref PubMed Scopus (188) Google Scholar Therefore, iron deficiency may not only have a direct effect on brain function and development, but may also decrease the availability of ketone bodies as an energy source.3Parkin P.C. Koroshegyi C. Mamak E. Borkhoff C.M. Birken C.S. Maguire J.L. et al.TARGet Kids! Collaboration. Association between serum ferritin and cognitive function in early childhood.J Pediatr. 2020; 217: 189-191Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar This possibility that the brain is deprived of ketone bodies as an energy source in iron deficiency indicates a need for further research into how iron is involved in brain development during early childhood. Association between Serum Ferritin and Cognitive Function in Early ChildhoodThe Journal of PediatricsVol. 217PreviewIn infants 1-3 years of age, we found higher serum ferritin values associated with higher cognitive function, as measured by the Mullen Scales of Early Learning (P = .02 for the nonlinear relationship). A serum ferritin of 17 μg/L corresponded to the maximum level of cognition, beyond which there was no meaningful improvement. Full-Text PDF