Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk

Abstract

This review analyzes the published evidence regarding maternal factors that influence the developmental programming of long-term adiposity in humans and animals via the central nervous system (CNS). We describe the physiological outcomes of perinatal underfeeding and overfeeding and explore potential mechanisms that may mediate the impact of such exposures on the development of feeding circuits within the CNS-including the influences of metabolic hormones and epigenetic changes. The perinatal environment, reflective of maternal nutritional status, contributes to the programming of offspring adiposity. The in utero and early postnatal periods represent critically sensitive developmental windows during which the hormonal and metabolic milieu affects the maturation of the hypothalamus. Maternal hyperglycemia is associated with increased transfer of glucose to the fetus driving fetal hyperinsulinemia. Elevated fetal insulin causes increased adiposity and consequently higher fetal circulating leptin concentration. Mechanistic studies in animal models indicate important roles of leptin and insulin in central and peripheral programming of adiposity, and suggest that optimal concentrations of these hormones are critical during early life. Additionally, the environmental milieu during development may be conveyed to progeny through epigenetic marks and these can potentially be vertically transmitted to subsequent generations. Thus, nutritional and metabolic/endocrine signals during perinatal development can have lifelong (and possibly multigenerational) impacts on offspring body weight regulation.

Keywords: adiposity; developmental programming; epigenetics; hypothalamus; obesity.

Graphical Abstract

Figure 1.

Effects of diet composition and caloric underfeeding and overfeeding during gestation and/or lactation on the programming of body weight in the offspring. Note that different conditions may lead to similar outcomes as indicated by the arrows pointing to the effect boxes. Abbreviations: IUGR, in utero growth restriction; BW, body weight; DIO, diet-induced obesity; HFD, high-fat diet. Figure created with BioRender.com.

Figure 2.

Comparison of brain development in humans (top) and rodents (bottom) from gestation to maturity. Humans and rodents experience similarly sequenced brain maturation but the timing is shifted to the right in rodents. At birth, humans have more mature brains than mice (by timing of neural events such as neurogenesis, synaptogenesis, and myelination (184), morphological observations (185), and transcriptional analysis (186)). In humans the peak brain growth rate occurs in the last 4 weeks of gestation but in mice this peak occurs in the second postnatal week. Figure created with BioRender.com.

Figure 3.

Developmental overnutrition effects on feeding circuits. Under conditions of maternal HFD feeding or overfeeding of offspring via reduced litter size during the early postnatal period, the offspring are more susceptible to obesity. This association could be mediated by mechanisms that include an augmented postnatal leptin surge, changes in the quality or quantity of neuronal connections within the feeding circuits, decrease in central leptin and insulin signaling, increase in ER stress within the ARH, decrease length of the hypothalamic primary cilia, alterations in synapses of POMC neurons, and decreased neuronal progenitor cell proliferation. Some or all of these mechanisms are likely affected by early overnutrition and contribute to subsequent susceptibility to obesity. Figure created with BioRender.com.

Figure 4.

Effects on body weight of transient hyperleptinemia. Transgenic mice that transiently overexpress leptin during the immediate postbirth period have no obvious phenotype until exposed to high-fat chow as adults. This exposure reveals a developmentally programmed susceptibility to increased weight gain on HFD compared with control littermates. When exposure to elevated leptin occurs in adults with a slow and gradual increase in leptin concentrations (to mitigate weight loss), the mice do not show any difference in body weight compared to controls even after HFD challenge. Figure created with BioRender.com.