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.
Highlights
Many epidemiological and experimental studies have demonstrated that a deficient or excessive provision of nutrients during in utero development and/or neonatal life increases the risk of developing the metabolic syndrome in adulthood
The rate of obesity, hypertension and insulin resistance is higher among individuals born at low birth weight than those of normal weight [1] and the offspring of dams exposed to nutrient restriction or overfeeding during pregnancy and/or lactation exhibit several physiological disturbances linked to the metabolic syndrome including insulin resistance [2,3,4], reduced leptin sensitivity [5], hepatic steatosis [6], hypertension [7,8] and hyperlipidemia [2,9]
After fasting for 48 h, the plasmatic levels of triglycerides, leptin and insulin decreased significantly in control rats and these changes were associated with a concomitant increase in the concentration of free fatty acids that returned to pre-fasting levels after re-feeding (Figure 2)
Summary
Many epidemiological and experimental studies have demonstrated that a deficient or excessive provision of nutrients during in utero development and/or neonatal life increases the risk of developing the metabolic syndrome in adulthood. The rate of obesity, hypertension and insulin resistance is higher among individuals born at low birth weight than those of normal weight [1] and the offspring of dams exposed to nutrient restriction or overfeeding during pregnancy and/or lactation exhibit several physiological disturbances linked to the metabolic syndrome including insulin resistance [2,3,4], reduced leptin sensitivity [5], hepatic steatosis [6], hypertension [7,8] and hyperlipidemia [2,9] These observations have been explained by the thrifty phenotype and the Developmental Origins of Health and Disease (DOHaD) hypothesis [10,11]. At the present time these putative gatekeepers are unknown, but it has been proposed that they might be transcription factors as well genes involved in the regulation of the epigenetic machinery or cell/tissue differentiation [25]
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