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Summary: Excess fat from a mother’s high-fat diet triggers immune cells to over-consume serotonin in the brains of developing males, leading to depression-like behaviors in the offspring.

What hasn’t been understood however is how the accumulation of fat tissue in mom might signal through the placenta in a sex-specific way and rearrange the developing offspring’s brain.

To fill this gap, Duke postdoctoral researcher Alexis Ceasrine, Ph.D., and her team in the lab of Duke psychology & neuroscience professor Staci Bilbo, Ph.D., studied pregnant mice on a high-fat diet.

In findings appearing November 28 in the journal Nature Metabolism, they found that mom’s high-fat diet triggers immune cells in the developing brains of male but not female mouse pups to overconsume the mood-influencing brain chemical serotonin, leading to depressed-like behavior.

Males, but not females, born by moms on a high-fat diet lacked a preference for simple syrup over tap water.

This rodent-like depression suggested to Ceasrine that mom’s nutrition while pregnant must have changed their male offspring’s brain during development.

Ceasrine and her team found that depressed-like male mice from high-fat diet moms had less serotonin in their brain both in the womb and as adults, suggesting these early impacts have lifelong consequences.

To see if microglia were overindulging in serotonin, Ceasrine analyzed the contents of their cellular “stomach”, the phagosome, with 3D imaging, and found that males born by moms on high-fat diets had microglia packed with more serotonin than those born to moms on a typical diet.

This indicated that elevated fat accumulation during pregnancy somehow signals through the male but not female placenta to microglia and instructs them to overeat serotonin cells.

To test if endotoxins could be the critical messenger from mom to enwombed males, the team measured their presence and found that, indeed, high-fat diets during pregnancy beefed up endotoxin levels in the placenta and their offspring’s developing brain.

Ceasrine said this may explain how fat accumulation triggers an immune response from microglia by increasing the presence of bacteria, resulting in overconsumed brain cells in male mice.

To see whether this may be true of humans as well, Ceasrine teamed up with Susan Murphy, Ph.D., a Duke School of Medicine associate professor in obstetrics and gynecology, who provided placental and fetal brain tissue from a previous study.

Just as the researchers observed in mice, they found that the more fat measured in human placental tissue, the less serotonin was detected in the brains of males but not females.

Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring

In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains

Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples