Maternal Metabolic Programming of the Developing Central Nervous System: Unified Pathways to Metabolic and Psychiatric Disorders

Abstract

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Maternal free fatty acid concentration during pregnancy is associated with newborn hypothalamic microstructure in humans

“…Fetal brain development culminates in the formation, segregation (differentiation/specialization), and integration (forming a network of networks) of key energy homeostasis networks (e.g., satiety) by the time of birth, at which time the foundational setting of these brain networks likely plays an especially meaningful role. Therefore, despite the small (in absolute terms) longitudinal sample size available for understanding the functional relevance of the observed newborn neurological phenotype (HTH MD), we assert that the observed association between newborn HTH MD and BF% in early childhood is of significant clinical relevance and that it warrants targeted external replication efforts, particularly given that this finding reaffirms a large body of preclinical evidence in support of the HTH being critical for energy homeostasis and showing a high degree in developmental plasticity and, consequently, phenotypic variation resulting from in utero exposures(12)(13)(14)(15)(16)(17)(18). Although it is unlikely that detailed measures of maternal sFFA concentrations across pregnancy such as those used here will be available for replication using large-scale, publicly available, longitudinal neuroimaging data, partial replication using more readily available but distal biomarkers such as maternal prepregnancy BMI could help further characterize the role of the HTH in the intergenerational transmission of obesity risk.Limitations of this study include the lack of cellular specificity provided by standard diffusion tensor imaging (DTI) measures, peripheral measures of circulating maternal sFFAs, partial characterization of the gestational milieu, and the specific focus on the HTH.…”

“…However, it remains unclear as to what degree the observed differences in the HTH of those with obesity relative to individuals with normal weight are a cause, consequence, or both of obesity. A rapidly growing and convergent body of preclinical evidence suggests that the HTH exhibits developmental plasticity, particularly during the fetal period, as it adapts to variation in maternal nutritional state (e.g., under/overnutrition) (12)(13)(14)(15)(16)(17)(18). This process may then influence postnatal metabolism and growth.…”

The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

“…Disruption to placental nutrient transport, either through poor maternal diet or stress during pregnancy, is recognised as a key contributor to programming of neurodevelopmental disorders, such as schizophrenia and affective disorders, in the offspring [ 75 ]. Although the original attention was in utero growth restriction (IUGR) resulting from extreme poor maternal diet as the consequence of famine [ 76 , 77 ], there is increasing evidence that overprovision by the mother can alter neurodevelopment in the offspring too [ 78 ].…”

Long-term obesogenic diet leads to metabolic phenotypes which are not exacerbated by catch-up growth in zebrafish

“…Metabolic syndrome is an umbrella term used for various pathologies surrounding long-term obesity such as hypertension or type 2 diabetes [ 1 ] and whether an individual develops obesity and metabolic syndrome is a complex interplay of genetic and environmental contributions. While studies suggest that heritable factors account for 40% to 85% of the variation in adiposity [ 2 ] the environmental contribution is still immense, even at birth [ 3 – 5 ]. Maternal body weight and overnutrition during the gestational period have been implicated in increasing the risk of metabolic syndrome for offspring [ 5 , 6 ].…”

“…While studies suggest that heritable factors account for 40% to 85% of the variation in adiposity [ 2 ] the environmental contribution is still immense, even at birth [ 3 – 5 ]. Maternal body weight and overnutrition during the gestational period have been implicated in increasing the risk of metabolic syndrome for offspring [ 5 , 6 ]. Further, high birth weight and/or rapid infant growth [ 7 , 8 ] as well as low birth weight / pre-term birth and a period of subsequent catch-up growth [ 9 – 11 ] are associated with an increased risk of metabolic syndrome later in life.…”