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Impaired Hypothalamic mTOR Activation in the Adult Rat Offspring Born to Mothers Fed a Low-Protein Diet

Abstract : Several epidemiological and experimental studies have clearly established that maternal malnutrition induces a high risk of developing obesity and related metabolic diseases in the offspring. To determine if altered nutrient sensing might underlie this enhanced disease susceptibility, here we examined the effects of perinatal protein restriction on the activation of the nutrient sensor mTOR in response to acute variations in the nutritional status of the organism. Female Wistar rats were fed isocaloric diets containing either 17% protein (control) or 8% protein (PR) throughout pregnancy and lactation. At weaning offspring received standard chow and at 4 months of age the effects of fasting or fasting plus re-feeding on the phosphorylation levels of mTOR and its downstream target S6 ribosomal protein (rpS6) in the hypothalamus were assessed by immuno-fluorescence and western blot. Under ad libitum feeding conditions, PR rats exhibited decreased mTOR and rpS6 phosphorylation in the arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei. Moreover, the phosphorylation of mTOR and rpS6 in these hypothalamic nuclei decreased with fasting in control but not in PR animals. Conversely, PR animals exhibited enhanced number of pmTOR imunostained cells in the paraventricular nucleus (PVN) and fasting decreased the activation of mTOR in the PVN of malnourished but not of control rats. These alterations occurred at a developmental stage at which perinatally-undernourished animals do not show yet obesity or glucose intolerance. Collectively, our observations suggest that altered hypothalamic nutrient sensing in response to an inadequate foetal and neonatal energetic environment is one of the basic mechanisms of the developmental programming of metabolic disorders and might play a causing role in the development of the metabolic syndrome induced by malnutrition during early life.
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Omar Guzman Quevedo, Raquel da Silva Aragao, Georgina Perez-Garcia, Rhowena J. B. Matos, André de Sa Braga Oliveira, et al.. Impaired Hypothalamic mTOR Activation in the Adult Rat Offspring Born to Mothers Fed a Low-Protein Diet. PLoS ONE, Public Library of Science, 2013, 8 (9), ⟨10.1371/journal.pone.0074990⟩. ⟨hal-02644055⟩

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