title: Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice.
abstract: The mechanisms that are essential for the maintenance of nutrient status in breast milk are unclear. Our data demonstrate that the intestine via hypoxia-inducible factor (HIF)-2α is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2α is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2α (but not HIF-1α) or the downstream target gene divalent metal transporter (DMT)-1 in lactating mothers did not alter systemic iron homeostasis in the mothers, but led to anemia, decreased growth, and truncal alopecia in pups which was restored following weaning. Moreover, pups born from mothers with a disruption of intestinal HIF-2α led to long-term cognitive defects. Cross-fostering experiments and micronutrient profiling of breast milk demonstrated that the defects observed were due to decreased maternal iron delivery via milk. Increasing intestinal iron absorption by activation of HIF-2α or parenteral administration of iron-dextran in HIF-2α knockout mothers ameliorated anemia and restored neonatal development and adult cognitive functions. The present work details the importance of breast milk iron in neonatal development and uncovers an unexpected molecular mechanism for the regulation of nutritional status of breast milk through intestinal HIF-2α.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Erik R
authors.initials: ER
authors.lastname: Anderson
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Angelical
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Brook
authors.initials: B
authors.lastname: Centofanti
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 shahy@umich.edu.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000740:Anemia / Q000209:etiology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D027682:Cation Transport Proteins / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007774:Lactation; D051379:Mice; D018345:Mice, Knockout; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D007501:Iron; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
keywords: HIF-2α; anemia; iron homeostasis; lactation; pregnancy