Impaired development of serotonergic and dopaminergic signaling
Maternal obesity may also increase the risk of neurodevelopmental and psychiatric disorders through abnormal development of the serotonergic (5-hydroxytryptamine or 5-HT) and dopaminergic (DA) systems. 5-HT signaling plays a significant role in neuronal migration, cortical neurogenesis, and synaptogenesis during fetal brain development.50,54 In murine and non-human primate models, offspring exposed to maternal high-fat diet had decreased 5-HT synthesis, and increased anxiety behavior, hyperactivity, and hypothalamic inflammation.31,48
Subclinical inflammation in maternal obesity may also decrease 5-HT production in offspring through increased breakdown of the 5-HT precursor tryptophan.50 In rodent models, pro-inflammatory cytokines have been demonstrated to reduce 5-HT neuron axonal density and embryonic neuronal survival in brain regions critical for behavioral regulation.55,56 Suppressed 5-HT synthesis has been observed in humans with ADHD, ASD, anxiety, and depression.31,48 Thus, altered 5-HT production may be one mechanism by which maternal obesity increases risk for neurodevelopmental disorders in offspring.
The dopaminergic system mediates reward neural circuitry and is similarly affected by maternal obesity. Rat offspring exposed to high-fat diets in utero had impaired mesolimbic dopaminergic signaling, resulting in impaired stress response and reward response to food.57,58 In mice, a maternal high-fat diet caused epigenetic changes in offspring DNA leading to dopamine dysregulation and changes in food preferences.59
Offspring changes in dopaminergic signaling may again be mediated through maternal inflammation; in a rat model of maternal inflammation, dopamine circuitry in offspring was dysregulated.60 Impaired dopaminergic signaling has been implicated in the development of ASD, ADHD, disordered eating, and other psychiatric disorders in humans.48
Maternal lifestyle and dietary changes, metformin treatment, and nutrient supplementation have all been explored as interventions to improve offspring neurodevelopment in maternal obesity.61-66 In animal studies, prepregnancy and lactational change from a high-fat diet to a control diet reduced offspring adiposity, circulating leptin, and anxiety behaviors.61 In a rat model of diet-induced obesity, maternal metformin treatment reduced fetal and placental inflammation.62 Observational data have pointed to polyunsaturated fatty acids, including omega-3 and omega-6 fatty acids, as possible candidate therapeutics in maternal obesity. Omega-3 fatty acids protect against brain inflammation and enhance serotonin signaling.31 Maternal omega-3 fatty acid deficiency has been associated with increased risk of offspring ASD and ADHD.63
A retrospective analysis of data from the Nursesâ Health Study II suggested that maternal intake of high levels of omega-6 fatty acids was associated with a 34% reduction in offspring ASD risk.65 Human pilot studies of obese maternal supplementation with omega-3 fatty acids have demonstrated reduction in maternal and placental inflammation.64 An ongoing clinical trial in obese pregnant women employs BMI-based prenatal micronutrient supplementation, with the goal of decreasing maternal and fetal oxidative stress and inflammation.66