Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

Abstract

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may "program" offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.

Keywords: anxiety; cognition; epigenetics; maternal high-fat diet; maternal obesity; microglia; neuroinflammation; perinatal programming; placenta.

Figure 1. Maternal high-fat diet programs offspring metabolism, neuroinflammation, and behavior. (A) Dams ate a low-fat (LFD) or high-fat diet (HFD) prior to breeding, and throughout pregnancy and lactation. HFD increased maternal body weight, and circulating leptin and proinflammatory cytokine (interleukin-6) concentrations. Offspring were assessed in adulthood following consumption of a LFD since weaning. (B) Adult offspring of dams fed a HFD had increased body weight and leptin, along with increased basal and LPS-induced proinflammatory cytokine (interleukin-1β) concentrations within the hippocampus. HFD offspring also had increased anxiety-like behavior in the elevated plus maze. (C) Adult offspring of dams fed a HFD showed morphological changes in microglia (Iba1 + cells) within the hippocampus, consistent with greater activation. These changes were apparent at baseline (absent an adult immune challenge), suggesting long-term programming of microglial function. Images are taken from the CA1 region of hippocampus. Scale bar = 50 um (top panels) and 12.5 um (bottom panels). Adapted from ref 46: Bilbo SD, Tsang V. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. FASEB J. 2010;24:2104-2115. Copyright © Federation of American Societies for Experimental Biology 2010

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, the production of proinflammatory cytokines by fetal placental macrophages (ie, Hofbauer cells),^, and the increased passage of circulating maternal glucocorticoids across the placenta, due to decreased 1 1-β-HSD2. Collectively, these conditions are associated with placental insufficiency or decreased placental perfusion, as well as intrauterine growth restriction.^, 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 acids), and the incorporation of saturated fatty acids and trans fats into the myelin of developing neurons. 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, 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).