PMID- 32173454
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20220531
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 88
DP  - 2020 Aug
TI  - Maternal obesity modulates sexually dimorphic epigenetic regulation and 
      expression of leptin receptor in offspring hippocampus.
PG  - 151-160
LID - S0889-1591(19)31512-0 [pii]
LID - 10.1016/j.bbi.2020.03.006 [doi]
AB  - Maternal obesity during pregnancy is associated with a greater risk for obesity 
      and neurodevelopmental deficits in offspring. This developmental programming of 
      disease is proposed to involve neuroendocrine, inflammatory, and epigenetic 
      factors during gestation that disrupt normal fetal brain development. The 
      hormones leptin and insulin are each intrinsically linked to metabolism, 
      inflammation, and neurodevelopment, which led us to hypothesise that maternal 
      obesity may disrupt leptin or insulin receptor signalling in the developing brain 
      of offspring. Using a C57BL/6 mouse model of high fat diet-induced maternal 
      obesity (mHFD), we performed qPCR to examine leptin receptor (Lepr) and insulin 
      receptor (Insr) gene expression in gestational day (GD) 17.5 fetal brain. We 
      found a significant effect of maternal diet and offspring sex on Lepr regulation 
      in the developing hippocampus, with increased Lepr expression in female mHFD 
      offspring (p < 0.05) compared to controls. Maternal diet did not alter 
      hippocampal Insr in the fetal brain, or Lepr or Insr in prefrontal cortex, 
      amygdala, or hypothalamus of female or male offspring. Chromatin 
      immunoprecipitation revealed decreased binding of histones possessing the 
      repressive histone mark H3K9me3 at the Lepr promoter (p < 0.05) in hippocampus of 
      female mHFD offspring compared to controls, but not in males. Sex-specific 
      deregulation of Lepr could be reproduced in vitro by exposing female hippocampal 
      neurons to the obesity related proinflammatory cytokine IL-6, but not IL-17a or 
      IFNG. Our findings indicate that the obesity-related proinflammatory cytokine 
      IL-6 during pregnancy leads to sexually dimorphic changes in the modifications of 
      histones binding at the Lepr gene promoter, and concomitant changes to Lepr 
      transcription in the developing hippocampus. This suggests that exposure of the 
      fetus to metabolic inflammatory molecules can impact epigenetic regulation of 
      gene expression in the developing hippocampus.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Glendining, K A
AU  - Glendining KA
AD  - Centre for Neuroendocrinology, Department of Anatomy, University of Otago, 
      Dunedin, New Zealand.
FAU - Higgins, M B A
AU  - Higgins MBA
AD  - Centre for Neuroendocrinology, Department of Anatomy, University of Otago, 
      Dunedin, New Zealand.
FAU - Fisher, L C
AU  - Fisher LC
AD  - Centre for Neuroendocrinology, Department of Anatomy, University of Otago, 
      Dunedin, New Zealand.
FAU - Jasoni, C L
AU  - Jasoni CL
AD  - Centre for Neuroendocrinology, Department of Anatomy, University of Otago, 
      Dunedin, New Zealand. Electronic address: christine.jasoni@otago.ac.nz.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200312
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (Leptin)
RN  - 0 (Receptors, Leptin)
SB  - IM
MH  - Animals
MH  - Diet, High-Fat
MH  - Epigenesis, Genetic
MH  - Female
MH  - Hippocampus
MH  - Leptin
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Obesity, Maternal
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects/genetics
MH  - Receptors, Leptin/genetics
OTO - NOTNLM
OT  - Cytokines
OT  - Developmental programming
OT  - H3K9me3
OT  - High-fat diet
OT  - Histones
OT  - Inflammation
OT  - Interleukin-6
OT  - Maternal nutrition
OT  - Neuroendocrine receptors
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/03/17 06:00
MHDA- 2021/04/28 06:00
CRDT- 2020/03/17 06:00
PHST- 2019/12/02 00:00 [received]
PHST- 2020/03/07 00:00 [revised]
PHST- 2020/03/08 00:00 [accepted]
PHST- 2020/03/17 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2020/03/17 06:00 [entrez]
AID - S0889-1591(19)31512-0 [pii]
AID - 10.1016/j.bbi.2020.03.006 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2020 Aug;88:151-160. doi: 10.1016/j.bbi.2020.03.006. Epub 2020 
      Mar 12.