Maternal obesity leads to increased proliferation and numbers of astrocytes in the developing fetal and neonatal mouse hypothalamus

Abstract

Maternal obesity during pregnancy is associated with chronic maternal, placental, and fetal inflammation; and it elevates the risk for offspring obesity. Changes in the development of the hypothalamus, a brain region that regulates body weight and energy balance, are emerging as important determinants of offspring risk, but such changes are only beginning to be defined. Here we focused on the hypothesis that the pathological exposure of developing hypothalamic astrocytes to cytokines would alter their development. A maternal high-fat diet (mHFD) mouse model was used to investigate changes in hypothalamic astrocytes in the fetus during late gestation and in early neonates by using immunochemistry, confocal microscopy, and qPCR. The number of astrocytes and the proportion of proliferating astrocytes was significantly higher in the arcuate nucleus (ARC) and the supraoptic nucleus (SON) of the hypothalamus at both ages compared to control offspring from normal weight pregnancies. Supplemental to this we found that cultured fetal hypothalamic astrocytes proliferated significantly in response to IL6 (10ng/ml), one of the cytokines significantly elevated in fetuses of obese dams, via the JAK/STAT3 signaling pathway. Thus, maternal obesity during pregnancy stimulated the proliferation and thereby increased numbers of astrocytes in the fetal as well as early neonatal hypothalamus, which may be driven, during fetal life, by IL6.

Effects of maternal obesity on placental function and fetal development

“…Animal models of high fat diet induced obesity demonstrate that offspring display social impairments, anxiety and depressive phenotypes with cognitive impairment and hyperactivity (Sullivan et al 2015). Similarly, increased proliferation was observed in the fetal hypothalamus when exposed to high levels of IL-6 in vivo and in vitro (Kim et al 2016). Elevated maternal TNF-α is associated with obesity (Stone et al 2014, Aye et al 2014b; Atègbo et al 2006), preterm birth and hyperlipidemia (Jelliffe-Pawlowski et al 2014) and elevated TNF-α from cord blood of preterm babies has been associated with cognitive deficits at 5 years of age (von Ehrenstein et al 2012).…”

“…Interestingly, 35% of children with autism also suffer from childhood obesity (Granich et al 2016), further linking the in utero environment with a predisposition for both neurodevelopmental and metabolic disorders. The observed behavioral and cognitive deficits in children of obese mothers may be linked to alterations in the serotonergic system and hypothalamic-pituitary-adrenal (HPA) axis resulting from increased pro-inflammatory cytokines and high fat diets (Kim et al 2016; Sullivan et al 2015; Ford et al 2009). …”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…HFD is provided to rodent dams 6–8 weeks before onset of pregnancy and lasts throughout gestation and often also throughout lactation, meaning that nutrients are transferred to the pups via the placenta and breast milk. Maternal HFD leads to an immediate increase in GFAP + cell density, proliferation, and mRNA levels in the arcuate and supraoptic hypothalamic nuclei of mouse neonates (gestational day 17.5 and P0; D. W. Kim, Glendining, Grattan, & Jasoni, ), and results in increased levels of perivascular GFAP coverage in the arcuate nucleus of P21 rats, suggesting elevated density of astrocytic processes around the blood vessels (Couvreur et al, ). Persistent effects of an early unhealthy diet on astrocytes have also been reported.…”

Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions

“…The mechanism behind this increase in tonic inhibitory synaptic input in PNHFD rats remains unclear, however. Astrocytes are known to shape synaptic strength and responsiveness and astroglial cells regulate and modulate the response of CNS nuclei, including the hypothalamus, to metabolic signals, and diet‐induced obesity . The astroglial toxin, fluoroacetate, induced an outward current in both control and PNHFD DMV neurons, suggesting that, as elsewhere in the central and peripheral nervous systems, astrocytes play a significant role in regulating neurotransmitter uptake and modulating synaptic strength.…”

“…Astrocytes are known to shape synaptic strength and responsiveness 45 and astroglial cells regulate and modulate the response of CNS nuclei, including the hypothalamus, to metabolic signals, 46 and diet-induced obesity. [47][48][49] The astroglial toxin, fluoroacetate, induced an outward current in both control and PNHFD DMV neurons, suggesting that, as elsewhere in the central and peripheral nervous systems, astrocytes play a significant role in regulating neurotransmitter uptake and modulating synaptic strength. The outward current induced in gastric-projecting DMV neurons in response to fluoroacetate was similar in PNHFD and control rats, however, implying that alterations in astrocyte morphology or function are unlikely to be responsible for the observed larger inhibitory synaptic currents.…”