title: Maternal high-fat diet and obesity compromise fetal hematopoiesis.
abstract: OBJECTIVE
  Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity.
  
  
  METHODS
  We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system.
  
  
  RESULTS
  Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration.
  
  
  CONCLUSIONS
  Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Ashley N
authors: AN
authors: Kamimae-Lanning
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Stephanie M
authors: SM
authors: Krasnow
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Natalya A
authors: NA
authors: Goloviznina
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Xinxia
authors: X
authors: Zhu
authors: Pulmonary & Critical Care, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Quinn R
authors: QR
authors: Roth-Carter
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Peter R
authors: PR
authors: Levasseur
authors: Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Sophia
authors: S
authors: Jeng
authors: Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Shannon K
authors: SK
authors: McWeeney
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Peter
authors: P
authors: Kurre
authors: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA ; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Daniel L
authors: DL
authors: Marks
keywords: Developmental programming; Fetal liver; Hematopoiesis; Hematopoietic stem and progenitor cells; High-fat diet; Obesity