Figure 2. Programming of brain and behavior by maternal high-fat diet involves inflammatory pathways, which interact with both the intrauterine and postnatal environments. In the placenta (inset depicts a schematic of a chorionic villus), these inflammatory mechanisms include the passage of elevated maternal cytokines through the placenta into the fetal circulation,¹²² the production of proinflammatory cytokines by fetal placental macrophages (ie, Hofbauer cells),^109,123 and the increased passage of circulating maternal glucocorticoids across the placenta, due to decreased 1 1-β-HSD2.¹²¹ Collectively, these conditions are associated with placental insufficiency or decreased placental perfusion, as well as intrauterine growth restriction.^115,116 In the developing brain, the inflammatory mechanisms include the microglial production of proinflammatory cytokines (as a result of activation of the TLR4-mediated signaling cascade by saturated fatty acids¹¹¹), and the incorporation of saturated fatty acids and trans fats into the myelin of developing neurons.¹³³ Thus, there is the promotion of a neuroinflammatory microenvironment, which may lead to oxidative stress, cell death, and an overall altered trajectory of brain development. Inflammatory mechanisms in both the placenta and the brain likely involve long-term epigenetic alterations, such as the hypomethylation of inflammatory genes, resulting in their increased transcription. Overall, increased levels of proinflammatory cytokines lead to decreased serotonin synthesis,¹²⁹ by the placenta during fetal development, and by the brain during postnatal development, which may contribute to the alteration of brain development and an increased risk of psychiatric disorders in adulthood (a risk that has been shown to be greater in males in human and animal models).