Maternal overnutrition and the regulation of energy balance and appetite before and after birth

Abstract

Based on a large series of epidemiological studies, it has been proposed that exposure to an increased nutrient supply before birth increases the risk of developing obesity in postnatal life. The physiological mechanisms underlying the association between increased nutrition before birth and later obesity are, however, poorly understood. This thesis has investigated the impact of an increased fetal nutrient supply on the programming of key systems within the appetite - regulating network and / or the adipocytes before and after birth. The studies in this thesis have demonstrated that plasma concentrations of the adipostatic hormone leptin are directly related to adiposity and the size of adipose cells in fetuses of ewes fed at or above maintenance energy requirements, which suggests that leptin may act as a peripheral signal of fat mass before birth. It has also been demonstrated that the components of the central network for appetite regulation are expressed in the hypothalamus of the fetal sheep from at least 110 d gestation ( term = 150 ± 3 d gestation ), and that the expression of the appetite - regulating neuropeptides is responsive to signals of increased nutrient supply before birth. This thesis has also demonstrated that an increase in maternal nutrition in late pregnancy results in increases in both food intake and glucose concentrations in the lamb in early postnatal life and in a significant increase in subcutaneous adiposity on postnatal day 30. Importantly, increased maternal nutrition resulted in an altered relationship between signals of increased fat mass and nutrition and expression of a central appetiteinhibitory neuropeptide, CART, in the lamb hypothalamus. It was also demonstrated that there was an interaction between the prenatal and postnatal nutritional environments in the determination of lipogenesis in the early postnatal period. The findings presented in this thesis provide evidence that programmed changes to the sensitivity of the appetite - regulating neuropeptides to signals of increased adiposity and nutritional status in early postnatal life are an important part of the physiological pathway through which exposure to an increased nutrient supply before birth may lead to an increased risk of obesity in later life.