The effect of fetal growth restriction and sex on the development and function of adipose tissue.

Abstract

A world-wide series of epidemiological studies has demonstrated that there is an association between being born small and the risk of visceral obesity, a more central deposition of subcutaneous fat and insulin resistance in adult life. In the lamb, intrauterine growth restriction (IUGR) results in a low birth weight and an increased visceral fat mass by 45d of postnatal life. In this thesis I have investigated the effect of IUGR on adipose tissue development and function during fetal and early postnatal life in the sheep. IUGR was induced by removal of the majority of endometrial caruncles in non pregnant ewes prior to mating which resulted in the subsequent placental restriction of fetal growth (PR). Fetal blood samples were collected from 116d gestation and visceral perirenal adipose tissue (PAT) collected from PR and control fetuses at 145d. In lambs IUGR was defined as a birth weight less than 2 standard deviations below the mean of a cohort of singleton Merino lambs. Blood samples were collected throughout the first 3 weeks of life and PAT and subcutaneous adipose tissue (SAT) was collected at 21 d. It was determined whether IUGR alters the expression of genes which regulate adipogenesis (IGF1, IGFR1, IGF2, IGFR2, PPARy, and RXRα), adipocyte metabolism (LPL, G3PDH, GAPDH) and adipokine signalling (leptin, adiponectin) in adipose tissue depots before and after birth using qRT-PCR. PR fetuses were hypoglycaemic, hypoinsulinaemic, hypoxic, and had a lower body weight than Control fetuses. The expression of both IGF1 and leptin mRNA in PAT, the major fetal adipose depot, was lower in the PR fetuses, although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus restriction of placental and hence fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue which may alter the functional development of the perirenal fat depot and contribute to altered leptin signalling in the growth restricted newborn and the subsequent emergence of an increased visceral adiposity. At 21d of postnatal life there was no increase in the relative mass of perirenal or subcutaneous fat in IUGR lambs compared with controls. Thus, this study has investigated the effect of IUGR on the development of adipose tissue prior to the development of an obese phenotype. At 21d of life there was a sex specific effect of IUGR on the expression of PPARy and leptin mRNA in perirenal visceral fat such that PPARy and leptin mRNA expression was decreased in male IUGR lambs, but not females. Interestingly PAT mass was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females at 21d. Thus, the nutritional environment before, and immediately after birth, may program adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and birth weight on PPARy and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life. At 21d of life there was no difference between Control and IUGR lambs in the relative mass of subcutaneous fat, or the expression of PPARy, RXRα, leptin, adiponectin, LPL, G3PDH, and GAPDH in subcutaneous fat at 21d of life. We have shown that the growth of the subcutaneous fat depot is related to plasma glucose, insulin and leptin concentrations, and to the development of perirenal fat. Thus, in contrast to perirenal adipose tissue, the postnatal, but not the fetal nutritional environment, programs subcutaneous adipocyte growth and gene expression. This thesis speculates that there may be a factor secreted from visceral fat that influences the development of the subcutaneous fat depot. At 21d of life there was also an effect of sex, but not IUGR, on the expression of IGF mRNA in adipose tissue. Male lambs had a higher expression of IGF1 mRNA in both PAT and SAT, and a higher expression of IGF1R and IGF2R in SAT compared with female lambs. It is likely that these differences in IGF mRNA levels reflect sexual dimorphism of the GH-IGF axis. When male and female lambs were combined there was a higher expression of IGF1 mRNA in SAT compared with PAT, and a higher expression of IGF2, IGF1R and IGF2R mRNA in PAT compared with SAT. These differences in IGF mRNA expression provide a potential mechanism to explain the sex and depot specific variations in mitogenic potency of IGF1 and proliferative capacities of preadipocytes, the regional variation in adipocyte metabolism, and the difference in incidence of visceral obesity between men and women in adult life.