Long-Term Sex-Dependent Vulnerability to Metabolic challenges in Prenatally Stressed Rats

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.

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats

“…Although clinical studies show a clear correlation of gestational (Entringer, Buss, & Wadhwa, 2010;Goldstein et al, 2016) and childhood stress (Agardh, Allebeck, Hallqvist, Moradi, & Sidorchuk, 2011;Danese & Tan, 2014;Thomas, Hypponen, & Power, 2008) with metabolic risk, whether the effects of ELS can be accurately replicated in animal models remains unknown. In agreement with our results, several reports have shown that PNS causes fasting hyperglycemia in adults (Detka et al, 2014;Lesage et al, 2004;Paternain et al, 2013), without further affecting glucose tolerance (Panetta et al, 2017). However, only a few reports have addressed the effect of MS180 on metabolic risk (Ruiz et al, 2018;Solas et al, 2010;Vargas et al, 2016).…”

Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease

“…This was interesting given the usual consensus that PNS combined with HF diet increases insulin resistance, overeating and obesity as suggested in some studies [16] , [57] . This may be again related to the window of intervention, since other studies focusing on different time-windows reported the opposite effect [12] , [51] , [58] . Altogether, while late gestation adversities appear to more profoundly affect females [14] , [15] , [16] and early gestation adversities appear to have more profound effects on males, whole pregnancy adversities appear to have strong and opposite effects for each sex, at least regarding metabolic responses to challenge.…”

Juvenile stress causes reduced locomotor behavior and dendritic spine density in the prefrontal cortex and basolateral amygdala in Sprague–Dawley rats

“…Animals subjected to prenatal stress showed an increase in this behavior at prepubertal and adult stages (Peters, 1986, Deminiére et al, 1992, Martinez-Tellez et al, 2009). In addition, several reports have shown an increase in the response to the stress of these animals through tests, such as elevated plus maze (Muhammad & Kolb, 2011;Panetta et al, 2017). However, postnatal stress, such as stress produced by maternal separation, depending on the stage of separation, can cause a reduction in locomotor activity in a new environment at prepubertal age without changes at adult age (Monroy et al, 2010) or not produce changes in locomotor activity (Aya-Ramos et al, 2017;Li, Robinson, & Bhatnagar, 2003) or produce an increase in locomotion in a new environment to adulthood (Soztutar et al, 2016).…”