title: Maternal high fat diet exposure is associated with increased hepcidin levels, decreased myelination, and neurobehavioral changes in male offspring.
abstract: Maternal obesity induces chronic inflammatory responses that impact the fetus/neonate during the perinatal period. Inflammation, iron regulation, and myelination are closely interconnected and disruptions in these processes may have deleterious effects on neurodevelopment. Hepcidin levels are increased in response to inflammation causing subsequent decreases in ferroportin and available iron needed for myelination. Our current studies were designed to test the hypotheses that: 1) maternal high fat diet (HFD) prior to and during pregnancy is sufficient to induce inflammation and alter iron regulation in the brain of the offspring, and 2) HFD exposure is associated with altered myelination and neurobehavioral deficits in the offspring. Our data revealed modest increases in inflammatory cytokines in the serum of dams fed HFD prior to pregnancy compared to dams fed a control diet (CD). Early increases in IL-5 and decreases in IL-10 were observed in serum at PN7 while IL-5 remained elevated at PN21 in the HFD-exposed pups. At PN0, most cytokine levels in whole brain homogenates were higher in the pups born to HFD-fed dams but were not different or were lower than in pups born to CD-fed dams at PN21. Conversely, the inflammation mediated transcription factor Nurr77 remained elevated at PN21. At birth, brain hepcidin, ferroportin, and l-ferritin levels were elevated in pups born to HFD-fed dams compared to pups born to CD-fed dams. Hepcidin levels remained elevated at PN7 and PN21 while ferroportin and l-ferritin levels were lower at PN7 and were not different at PN21. Decreases in myelination in the medial cortex were observed in male but not in female pups born to maternal HFD-fed dams at PN21. These structural changes correlated with changes in behavior (novel object recognition) in at 4months in males only. Our data indicate that maternal obesity (HFD) results in disruption of iron regulation in the brains of the offspring with structural and neurobehavioral deficits in males.
authors: Centers for Perinatal Research, The Research Institute at Nationwide Children's Hospital, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: Amanda E
authors: AE
authors: Graf
authors: Centers for Perinatal Research, The Research Institute at Nationwide Children's Hospital, United States.
authors: Scott W
authors: SW
authors: Lallier
authors: Centers for Perinatal Research, The Research Institute at Nationwide Children's Hospital, United States.
authors: Gavisha
authors: G
authors: Waidyaratne
authors: Department of Pediatrics, The Ohio State University, Columbus, OH, United States.
authors: Michael D
authors: MD
authors: Thompson
authors: Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States.
authors: Trent E
authors: TE
authors: Tipple
authors: Centers for Perinatal Research, The Research Institute at Nationwide Children's Hospital, United States.
authors: Mark E
authors: ME
authors: Hester
authors: Department of Pediatrics, The Ohio State University, Columbus, OH, United States; Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors: Aaron J
authors: AJ
authors: Trask
authors: Centers for Perinatal Research, The Research Institute at Nationwide Children's Hospital, United States; Department of Pediatrics, The Ohio State University, Columbus, OH, United States. Electronic address: Lynette.Rogers@Nationwidechildrens.org.
authors: Lynette K
authors: LK
authors: Rogers
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004660:Encephalitis / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D064451:Hepcidins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000523:psychology*; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology; D012727:Sex Characteristics
chemical_list: D016207:Cytokines; D064451:Hepcidins; D012333:RNA, Messenger; D007501:Iron
keywords: Hepcidin; High fat diet; Inflammation; Maternal obesity; Neurodevelopment