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 HFDexposed 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 4 months 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.

A Review of the Impact of Maternal Obesity on the Cognitive Function and Mental Health of the Offspring

“…This effect was also observed in offspring exposed to a high fat diet throughout both the pre- and postnatal period, who showed decreased retention times, higher escape latencies, and less time spent in the target quadrant of the water maze, suggesting impaired spatial memory performance [22,24,25,26]. Similarly contradictory findings have been described using the novel object recognition task, with one experiment reporting decreased exploration of the novel object in young adult male—but not female—offspring of obese dams [44] and another reporting higher initial novel exploration by male offspring exposed to a cafeteria diet during lactation [21]. Again, these discrepancies may relate to the timing of dietary exposure, sex, and age of offspring at testing.…”

Adverse neuropsychiatric development following perinatal brain injury: from a preclinical perspective

“…Similarly to hyperoxia, maternal obesity and neonatal HI increase cytokine levels in the offsprings' brain. This was demonstrated in rodent and non-human primate models of obesity 34,154,155 . Moreover, after neonatal hypoxic-ischaemic brain injury in rodents, cerebral levels pro-inflammatory proteins (e.g.…”

Cafeteria diet during the gestation period programs developmental and behavioral courses in the offspring

“…In our study some parameters of physical and neurobehavioral development were delayed in both male and female offspring. Birth through 21 days is a time of active brain growth, extension of neuronal processes, migrating oligodendrocytes and myelination (Graf et al, 2016). Possibly, the deficit in neurobehavioral reflex ontogeny should be associated with delayed myelination since previous studies have shown that maternal high fat diet prior to and during pregnancy is associated with decreased myelination in some brain regions (Graf et al, 2016).…”