Abstract
Prenatal stress (PNS) might affect the developmental programming of adult chronic diseases such as metabolic and mood disorders. The molecular mechanisms underlying such regulations may rely upon long-term changes in stress-responsive effectors such as Brain-Derived Neurotrophic Factor (BDNF) that can affect neuronal plasticity underlying mood disorders and may also play a role in metabolic regulation. Based upon previous data, we hypothesized that PNS might lead to greater vulnerability to an obesogenic challenge experienced at adulthood. In order to investigate our hypothesis, pregnant Sprague-Dawley female rats underwent a chronic procedure of restraint stress during the last week of gestation. The adult offspring were then challenged with a high fat diet (HFD) over 8 weeks and tested for metabolic and emotional endpoints. Moreover, brain specific changes in Bdnf expression levels were also assessed. Overall, HFD resulted in increased caloric intake, insulin resistance, impaired glucose tolerance and higher circulating levels of leptin, while PNS increased the leptin/adiponectin ratio, an index of metabolic risk in adult male subjects. Interestingly, HFD consumption increased anxiety-like behaviors in the Elevated Plus Maze, particularly in males, and this effect was buffered by PNS. Levels of Bdnf were finely modulated by PNS and HFD in a region- and sex-dependent fashion: female offspring overall showed greater plasticity, possibly mediated through increased total Bdnf mRNA expression both in the hippocampus and in the hypothalamus. In conclusion, while the experience of maternal stress during intrauterine life promotes metabolic dysfunction induced by a HFD at adulthood, the interaction between PNS and HFD is positive in male subjects, and in agreement with the match-mismatch hypothesis, resulting in a reduction of anxious behaviors.
Highlights
A suboptimal intrauterine environment can program adult chronic diseases predisposing the offspring to develop metabolic and mood disorders later in life (Barker, 1995)
We evaluated the gene expression of total and long 3′UTR Bdnf mRNA in both ventral hippocampus and hypothalamus as this neurotrophic factor is involved in both energy metabolism and neural plasticity underlying anxiety-like behavior (Cirulli and Alleva, 2009; Tamashiro and Moran, 2010; Paternain et al, 2013; Mou et al, 2015)
Here we show that: (1) immobilization stress during pregnancy led to a reduction in placental weight and 11β-HSD2 mRNA expression, fetal growth retardation and to abnormal body weight up to the juvenile period only in males (PND-7) as a possible result of sex-dependent developmental perturbation induced by prenatal stress (PNS) and that (2) when the L/A metabolic risk marker was analyzed at adulthood, PNS induced a strong vulnerability to high fat diet (HFD) in males but not in females; in general, exposure to HFD increased leptin and adiponectin blood levels in both sexes and led to reduced insulin sensitivity and glucose tolerance, with greater effects in the male offspring
Summary
A suboptimal intrauterine environment can program adult chronic diseases predisposing the offspring to develop metabolic and mood disorders later in life (Barker, 1995). A differential sex-dependent response has been observed demonstrating that PNS female and male rats are programmed to respond differently to an imposed restraint stress at adulthood (Bowman et al, 2004). Brain structures, such as the hippocampus, that play a role in many aspects of metabolic and mood disorders, show a sexdependent development and are differentially affected by PNS in male and female offspring predisposing toward a disturbed hippocampal neuroplasticity (Darnaudéry and Maccari, 2008; Cirulli, 2017)
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