Skip to main content
. Author manuscript; available in PMC: 2020 May 22.
Published in final edited form as: Front Neuroendocrinol. 2020 Feb 18;57:100834. doi: 10.1016/j.yfrne.2020.100834

Table 2.

Findings from animal models of maternal overnutrition. Models of maternal overnutrition are presented with resulting changes to offspring behavior, brain, and peripheral outcomes; maternal physiology; and placental physiology. Studies referenced are limited to the present review.

Ref Species (Strain) Model Offspring Behavioral Phenotype Offspring Physiology, Central Offspring Physiology, Peripheral Maternal Physiology Placental Physiology Notes
(Winther et al., 2018) Rat [Sprague- Dawley (SD)] 60% High-Fat Diet (HFD), 8 w pre-conception (PC) through gestation (G) and lactation (L) Anxiety-like behaviour Hippocampus

  • ↑ Corticotropin releasing hormone receptor 2 mRNA

  • ↓ Mineralocorticoid receptor mRNA

  • ↑ Pro-inflammatory cytokine mRNA

  • Alterations in kynurenine pathway gene expression

 Pre- / at weaning

  • ↑ Body weight (BW)

Adult

  • ↑ bw ♂

  • ↑ BW

 _
(Musial et al., 2017) Mouse (C57) 30% kcal fat, 36% kcal sugar (HFHS diet), through G
Dam sacrifice G16 or G19		 - - Fetal, G16

  • ↑ BW

Fetal, G19

  • ↔ BW

 G16

  • ↑ Blood glucose

  • ↑ Plasma insulin

  • ↑ Plasma leptin

  • ↑ Plasma cholesterol

G19

  • ↓ Plasma free fatty acids (FFA)

  • ↓ Glucose tolerance

  • ↓ Insulin sensitivity

  • ↓ Weight (G16, G19)

  • ↓ Prolactin /placental lactogen-related mRNA (G19)
(Sun et al., 2012) Rat(SD) 60% HFD, through G and L; Offspring cross-fostered to same- or opposite-diet dam at PI

  • HFD-HFD (G-L)

  • Control diet (Con)- HFD

  • HFD-Con

 - Hypothalamus, pre- /atweaning

  • ↓ Leptin sensitivity at P10 (any HFD exposure ♂, G HFD ♀)

  • ↑ Baseline pSTAT3 (L HFD ♀)

  • ↓ Leptin sensitivity at P21 (L HFD)

 Pre- /at weaning, L HFD

  • ↑ BW

  • ↑ Adiposity

  • ↑ Plasma leptin

  • ↓ Glucose tolerance

Adult, L HFD

  • ↑ BW (♂)

  • ↑ Adiposity (♂)

  • ↑ Plasma leptin (P10)

  • ↑ Milk leptin (P21)

  • ↑ Milk fat content(P21)

 - Differential effects by exposure window: ↑ impact on offspring metabolic phenotype with L HFD
(Niculescu and Lupu, 2009) Mouse (C57) 60% HFD, 10 w PC through G
Dam sacrifice G17		 - Hippocampus, fetal

  • ↑ Neural progenitor proliferation (neuroepithelium)

  • ↓ Neural progenitor proliferation (dentate gyrus, DG)

  • ↓ Neuronal differentiation (DG)

Cortex, fetal

  • ↑ Neural progenitor proliferation (neuroepithelium)

 Fetal

  • ↓ BW

  • ↑ Fetal resorption

  • ↑ BW

 -
(Tozuka et al., 2010) Mouse (C57) 57.5% HFD, 6 w PC through G and L until P16 Cognitive impairment (adolescent) Hippocampus, adolescent

  • ↑ Peroxidized lipid accumulation

  • ↓ BDNF mRNA/protein

  • Impaired dendritic arborization of neurons

 -

  • ↑ BW

  • ↑ Serum cholesterol

  • ↑ Serum FFA

  • ↑ Serum triglycerides (TG)

 - Cognitive phenotype normalized by adulthood
(Wright et al., 2011) Rat (Wistar) Cafeteria diet, 11 w PC through G and L 8 experimental groups limiting HFD to PC, G, L, or a combination of exposure windows (e.g. PC & L only) Decreased anxiety-like behavior (L exposure, ♂) -

  • ↑ Adiposity (L exposure)

  • ↑ BW (PC exposure)

 - Differential effects by exposure window
(Cordner et al., 2019) Rat (SD) 60% HFD, through G and L Cognitive impairment Hippocampus, weaning

  • ↓ Insr mRNA

  • ↓ Lepr mRNA

  • ↓ Slc2al mRNA

Hippocampus, adult

  • ↓ Insr mRNA

  • ↓ Lepr mRNA

  • ↑ BW

 - -
(White et al., 2009) Rat (Long Evans) 60% HFD, 4 w PC through G and L Offspring placed as adults onto HFD or Con Cognitive impairment (HFD offspring exposed to adult HFD) With maternal HFD

  • ↑ markers oxidative stress

  • ↓ IL-6 cortex

  • ↑ BW (HFD offspring exposed to adult HFD)

  • ↑ adiposity (with maternal HFD)

  • ↑ BW

 - Maternal + offspring diet exposure
(Can et al., 2012) Rat(SD) 65% HFD, through G and L Offspring weaned onto respective dam diet Anxiety-like behavior Depression-like behavior Cognitive impairment Hippocampus

  • ↓ Number pyramidal neurons

  • ↑ Serum TG

 - - Maternal + offspring diet exposure
(Robb et al., 2017) Rat (SD) 45% HFD, 10 w PC through G and L Cognitive impairment (adolescent ♂, trend in adult ♂) -

  • ↑ Fasting blood glucose (♀)

  • ↑ BW

  • ↑ Adiposity

  • ↑ Plasma leptin

  • ↓ Glucose tolerance

 Cognitive phenotype normalized by adulthood; Sex differences: ↑ effect ♂
(Moser et al., 2017) Rat (Long Evans) 60% HFD, 6 w PC through G and L Cognitive impairment - Pre- /at weaning

  • ↑ BW

  • ↑ BW

 -
(Page et al., 2014) Rat (SD) 45% HFD, 1 m PC through G and L
Offspring weaned onto HFD or Con		 Cognitive impairment (maternal HFD exposure) Hippocampus, maternal HFD exposure

  • ↓ BDNF mRNA/protein

  • ↓ nerve growth factor mRNA/protein

  • ↓ Arc mRNA/protein

  • ↓ Synaptophysin mRNA

  • ↑ Synaptotagmin mRNA

  • ↓ Glutamate NMDA receptor 2b

 Maternal HFD exposure

  • ↑ BW

  • ↑ Adiposity

  • ↑ Plasma CORT

  • ↑ Serum glucose (only if weaned to HFD)

 - -
(Bilbo and Tsang, 2010) Rat (SD) 60% high saturated fat HFD (SFD) or 60% high trans fat HFD (TFD), 4 w PC through G and L Anxiety-like behavior (SFD or TFD ♂) Improved cognitive performance (SFD or TFD ♂) Hippocampus, neonate

  • ↑ Microglial activation markers mRNA

Hippocampus, weaning

  • ↑ Basal, LPS-stimulated IL-1β (SFD)

Hippocampus, adult

  • ↑ Basal microglial activation (SFD)

  • ↑ Microglial LPS reactivity (SFD > TFD) Pre- /at weaning

 Pre- /at weaning

  • ↑ BW (SFD)

  • ↑ Plasma leptin (SFD > TFD)

Adult

  • ↑ BW (SFD ♂)

  • ↑ Plasma leptin (SFD > TFD ♂, SFD ♀)

  • ↑ BW

  • ↑ Plasma leptin (SFD)
(Graf et al., 2016) Mouse (C57) 60% HFD, 8 w PC through G and L Cognitive impairment (♂) Pre- /at weaing

  • ↑ Pro-inflammatory cytokine mRNA

  • ↑ Nurr77 mRNA (inflammation-mediated TF)

  • Changes to iron metabolism-related gene expression

  • ↓ Myelination media cortex (♂)

 Pre- /at weaning

  • ↑ BW

  • ↑ Serum IL-5

  • ↓ Serum IL-10

  • ↑ BW

  • ↑ Serum leptin

  • ↑ Circulating proinflammatory cytokines

 - Sex differences: ↑ effect ♂
(Kang et al., 2014) Mouse (C57) 60% HFD,

  • 6 w PC through G and L (HFD-HFD), OR

  • 6 w PC through G only (HFD-Con), OR

  • Through L only (Con-HFD)

 Anxiety-like behavior (♀; HFD-HFD, HFD-Con) Social interaction deficits (♀; HFD-HFD only)
Hyperactivity (♂; HFD-HFD, HFD-Con)		 Adult

  • ↑ Microglial activation in whole brain and amygdala (♀, HFD-HFD)

  • ↑ Pro-inflammatory cytokines (♀, HFD-HFD)

  • ↑ BW P21 (HFD-HFD)

  • ↑ BW adolescence (HFD-HFD, HFD-Con)

  • ↑ BW with PC/G exposure

 - Timing of exposure: ↑ impact PC/G v L HFD, partial mitigation with L switch
(Buffington et al., 2016) Mouse (C57) 60% HFD, 8 w PC through G and L Social interaction deficits

  • ↓ Oxytocin in hypothalamus

  • ↓ Social interaction-induced LTP in VTA DA neurons

  • Gut dysbiosis

  • ↑ BW

 -
(Sasaki et al., 2013) Rat (Long Evans) 60% HFD, 4 w PC through G and L Anxiety-like behavior Amygdala

  • ↑ Mineralocorticoid receptor mRNA (♀)

  • ↑ Glucocorticoid receptor mRNA (♀)

  • ↑ Pro-inflammatory gene mRNA

  • ↑/↓ Anti-inflammatory gene mRNA

Hippocampus

  • ↓ Anti-inflammatory mRNA (♀)

 Pre- /at weaning

  • ↑ BW

Adult

  • ↔BW

  • ↓ Baseline CORT

  • ↑ CORT elevation following stress challenge

  • ↑ BW

 - Timing of offspring effect: altered phenotype in adolescent (Sasaki et al., 2014) v adult animals
(Sasaki et al., 2014) Rat (Long Evans) 60% HFD, 4 w PC through G and L Decreased anxiety-like behavior (adolescent) Amygdala, adolescent

  • ↓ Pro-inflammatory gene mRNA (♀

  • ↓ Anti-inflammatory gene mRNA

Hippocampus, adolescent

  • ↑ Glucocorticoid receptor mRNA

  • ↑ Pro-inflammatory cytokine mRNA

  • ↑ Anti-inflammatory gene mRNA

 Pre- /at weaning

  • ↑ BW

Adolescent

  • ↔BW

  • ↑ BW

 - Timing of offspring effect: altered phenotype in adolescent v adult (Sasaki et al., 2013) animals
(Giriko et al., 2013) Rat (Wistar) 52% HFD, through L Delayed reflex development (early life)
Depression-like behavior (adult)		 - Pre- / at weaning

  • ↔ BW

  • ↓ Mediolateral head axis

  • ↑ BW

Adult

  • ↓ Anteroposterior head axis

  • ↔ BW

 -
(Lin et al., 2015) Rat (SD) 45% HFD, 10 d PC through G and L Adult offspring subjected to chronic unpredictable mild stress (CUMS) Sensitization to stress-induced depression-like behavior

  • ↑ CUMS-associated ↑ in CSF calcitonin gene-related peptide

  • ↑ CUMS-associated ↑ in hippocampal calcitonin gene-related peptide

  • ↔ BW bymaternal diet

  • ↑ CORT in restraint challenge

  • ↓ CORT response habituation torepeated restraint

  • ↑ BW

 Maternal HFD ↑ sensitization to stress
(Zieba et al., 2019) Mouse (C57) 43% HFD, 5 w PC through G and L Facilitation of PPI -

  • ↑ BW

  • ↑ BW

 -
(Wolfrum and Peleg-Raibstein, 2018) Mouse (C57) 60% HFD, 3 w PC through G and L Cognitive impairment (adult, ↑ severity in aged adult)Facilitation of PPI (adult, aged adult) Ventral hippocampus, adult

  • ↓ Glutamate

  • ↓ Tyrosine

  • ↓ Taurine

Medial PFC, adult

  • ↓ GABA

  • ↓ Aspartate

  • ↓ Taurine

 - - -
(Song et al., 2017) Rat(SD) 60% HFD, through G - - -

  • ↔ BW

  • ↑ Adiposity

  • ↑ Plasma leptin

  • ↓ Plasma adiponectin

  • ↓ Plasma triglycerides

  • ↓ Glucose tolerance

  • ↓ Labyrinth thickness

  • ↑ Nutrient transporter mRNA and protein ♂

  • ↑ Growth-related mRNA ♀

  • ↔ Weight
(Sun et al., 2014) Rat(SD) 60% HFD, through G and L - Hypothalamus, pre- /at weaning

  • Baseline alterations to leptin signaling pathway mRNA (↓ ObRb, ↓ STAT3, ↑ SOCS3)

  • ↓ Leptin sensitivity in arcuate

  • ↓ Appetite-related genes mRNA (NPY, AgRP)

Hypothalamus, adult

  • ↓ ObRb ♂

  • ↓ CRH mRNA ♂

 Pre- / at weaning

  • ↑ BW

  • ↑ Adiposity

  • ↑ Plasma leptin

  • ↑ Plasma triglycerides

  • ↓ Plasma cholesterol

  • ↑ Glucose tolerance

Adult

  • ↔ BW

  • ↑ Adiposity

  • ↑ Plasma leptin ♂

  • ↔ BW

  • ↑ Adiposity

  • ↑ Plasma leptin

  • ↑ Milk leptin

 -
(Schmitz et al., 2018) Mouse (C57) 60% HFD, 9–11 w PC through G and L - Hippocampus, adult

  • ↓ Insulin signaling pathway components (insulin resistance)

  • ↓ Neurogenesis

  • ↓ Synaptic plasticity markers

 Pre- /at weaning

  • ↑ BW

  • ↑ Adiposity

  • ↑ Serum insulin

  • ↓ Glucose tolerance

Adult

  • ↔ BW

  • ↔ Adiposity

  • ↔ Serum insulin

  • ↔ Glucose tolerance

  • ↑ BW

 -
(Ford et al., 2009) Sheep 150% of recommended intake sheep diet by body weight, 60 d PC through G Dam sacrifice mid-gestation (G75 of 150 d G course) - - Fetal

  • ↑ BW, length

  • ↑ Plasma glucose

  • ↑ serum insulin

  • ↑ serum CORT

  • ↑ BW

  • ↑ adiposity

  • ↑ plasma glucose & serum insulin at baseline

  • ↓ glucose tolerance

  • ↑ serum CORT
Mouse (C57) 60% HFD, through G - - Fetal

  • ↑ BW

  • ↑ triglycerides
(Qiao et al., 2015)

  • ↑ adiposity

  • ↑ serum free fatty acids

  • ↑ adiposity

  • ↓ serum triglycerides

  • ↑ serum insulin

  • ↑ lipoprotein lipase mRNA, protein, activity

  • ↑ lipid transport genes mRNA

  • ↑ lipogenic transcription factors

  • ↓ SIRT1
(Sanders et al., 2014) Mouse (C57) 45% HFD, 8 w PC through G - Hypothalamus, fetal

  • ↓, NPY innervation of paraventricular nucleus

  • Altered arcuate mRNA levels of neurite growth regulators

 Fetal

  • ↑ BW

  • ↑ plasma IL-6

  • ↑ BW

  • ↑ plasma IL-6

 -
(Edlow et al., 2018) Mouse (C57) 60% HFD, 12–14 w PC through G - Fetal

  • ↑ microglia number

  • ↑ microglial reactivity to LPS immune challenge(♂)

 Fetal

  • ↔ Fetal BW

  • ↑ BW

  • ↑ CDllb + macrophage reactivity to LPS immune challenge (♂)

  • ↔ weight
(Kim et al., 2016) Mouse (C57) 45% HFD, 8 w PC through G - Hypothalamus, fetal

  • ↑ astrocyte proliferation, number in arcuate and supraoptic nucleus

Hypothalamus, neonate

  • ↑ astrocyte proliferation, number in arcuate and supraoptic nucleus

 - - -
(D’Asti et al., 2010) Rat(SD) 30%* by weight high n-6 fat HFD OR 30% by weight high n-3 fat HFD, GD 14 through L;* By % weight; % kcal fat not reported - Hypothalamus, pre-weaning

  • ↓ arachidonic acid content (n-3 HFD)

Hippocampus, pre-weaning

  • ↓ arachidonic acid (n-3 HFD)

  • ↓ endocannabinoids (n-3 HFD)

 Pre- / at weaning

  • ↑ BW (n-6 HFD)

  • ↑ plasma leptin (n-6 HFD)

  • ↑ subcutaneous fat depot leptin mRNA (n-6 HFD)

  • ↑ baseline plasma CORT

  • ↑ stress-induced CORT AUC (n-3 HFD)

  • ↓ n-6/n-3 ratio in milk (n-3 HFD)

 -
(Abuaish et al., 2018) Rat (Long Evans) 60% HFD, 3 w PC through G and L Anxiety-like behavior (neonate) PVN, pre- /at weaning

  • ↑ corticotropin releasing hormone mRNA

Ventral hippocampus, pre-/at weaning

  • ↓ glucocorticoid receptor

mRNA		 Pre- /at weaning

  • ↑ BW

  • ↑ stress-induced CORT at P7

  • ↑ stress-induced ACTH elevation, absence of CORT response at P13

  • ↑ BW

  • ↑ stress-induced CORT peak

  • ↑ nursing time, dark cycle

 -
(Walker et al, 2008) Rat (SD) 30%* by weight HFD, GD 14 through L; * By % weight; % kcal fat not reported - - Pre- /at weaning

  • ↑ plasma leptin

  • ↑ adiposity

  • ↑ BW

Adult

  • ↑ plasma leptin

  • ↑ BW

  • ↑ basal CORT, dark cycle

 - -
(Niu et al, 2019) Rat (SD) 27.5%* by weight HFD, 10 d PC through G and L; *By % weight; % kcal fat not reported - Hypothalamus

  • ↑ basal corticotropin releasing hormone mRNA in paraventricular nucleus

  • ↑ corticotropin releasing hormone mRNA in paraventricular nucleus following repeated restraint stress

Amygala

  • ↑ glucocorticoid receptor

  • ↑ plasma CORT across light/dark cycle, f pulse # and pulse amplitude CORT secretion

  • ↑ restraint and LPS challenge CORT, ↔ insulin-induced hypoglycemia challenge CORT

  • ↓ CORT response habituation to restraint stress

 - -
(Frias et al., 2011) Non-Human Primate (Japanese macaque) 32% HFD, ≤ 4y PC through G - - Fetal, sensitive/obese

  • ↑ stillbirthn

 Sensitive/obese dams

  • ↑ BW

  • ↑ plasma insulin

  • ↓ glucose tolerance

  • ↑ plasma leptin

All HFD (sensitive/obese and resistant/lean)

  • ↑ plasma TG

 Sensitive/obese dams

  • ↓ fetal side blood flow

  • ↑ infarction

All HFD (sensitive/obese and resistant/lean)

  • uteroplacental blood

  • perfusion

  • ↑ TG

  • ↑ pro-inflammation (↑ TLR4, ↑ MCP-1, ↑ IL-lβ)
(Thompson etal., 2017) Non-Human Primate (Japanese macaque) 32% HFD + calorically dense treats, ≥ 1 y PC through G and L; Offspring weaned to HFD or Con Anxiety-like behavior (juvenile, with maternal HFD) Increased stereotypic behaviors (juvenile, postweaning HFD) Dorsal raphe, juvenile

  • ↓ TPH2 (with maternal HFD)

Median raphe, juvenile

  • ↑ TPH2 (with postweaning HFD)

Prefrontal cortex, juvenile

  • ↓ 5-HT immunoreactivity (with postweaning HFD)

 Pre- /at weaning

  • ↑ hair cortisol Juvenile

  • ↑ plasma cortisol (with postweaning HFD)

  • ↑ pre-pregnancy BW

  • ↓ glucose tolerance

  • ↑ plasma insulin

  • ↑ plasma leptin

 - Differential effects of maternal and postweaning HFD
(Hayes et al., 2014) Rat (SD) 45% HFD, 16 w PC through G - - -

  • ↑ monocyte chemoattractant protein 1 (MCP-1), marker of systemic inflammation

  • ↑ trophoblast invasion

  • Impaired spiral artery remodeling

  • ↑ matrix metalloproteinase

  • 9
(Mark et al., 2011) Rat (Wistar) 45% HFD, through G - - Fetal

  • ↓ bw

  • ↑ plasma leptin

  • ↑ BW gain

  • f↑ adiposity

  • ↑ plasma leptin

  • ↓ junctional weight

  • ↔ markers of vascular development
(Sullivan et al., 2010) Non-Human Primate (Japanese macaque) 32% HFD + calorically dense treats, ≤ 4 y PC through G Anxiety-like behavior (♀, infant) Dorsal raphe, fetal

  • 5-HT system perturbations (↑ TPH2 mRNA, ↑ 5-HT1AR mRNA)

Juvenile

  • ↓ CSF 5-HT

 - - -
(Peleg-Raibstein et al., 2012) Mouse (C57) 60% HFD, 3 w PC through G and L Anxiety-like
behavior		 Dorsal hippocampus

  • ↑ BDNF

Ventral hippocampus

  • ↑ 5-HT1AR

  • ↑ GABAAR α2

 - - -
(Mao et al., 2010) Mouse (NIH Swiss) 60% HFD, 30–35 w PC through G (sacrifice at mid-gestation) - - -

  • ↑ BW

  • Sexual dimorphism in placental gene expression, ♀ more altered than ♂
(Thompson et al., 2018) Non-Human Primate (Japanese macaque) 32% HFD + calorically dense treats, ≥ 1 y PC through G and L Anxiety-like behavior (juvenile) -

  • ↑ Systemic proinflammatory profile in gestation

  • ↑ Pre-pregnancy adiposity

  • ↓ Glucose tolerance

 - -