Erhuma A, Salter AM, Sculley DV, Langley-Evans SC, Bennett AJ. Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol Endocrinol Metab 292: E1702-E1714, 2007. First published February 13, 2007; doi:10.1152/ajpendo.00605.2006.-The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low-protein (LP) diet, targeted to early (LPE), mid-(LPM), or late (LPL) pregnancy, or throughout gestation (LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP-exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP-programmed hypertriglyceridemia and insulin resistance. All LP-exposed groups exhibited histological evidence of hepatic steatosis and were found to have twoto threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age-related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPAR␥, and PPAR␣ and their respective downstream target genes ACC1, FAS, L-PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPAR␥ and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome-like phenotype that develops only with senescence. The data implicate altered expression of SREBP-1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified. pregnancy; lipids; transcription factors; insulin resistance; metabolic syndrome THE ENVIRONMENT ENCOUNTERED in fetal life is an important determinant of disease risk in adult life (25). Exposure to less than optimal nutrition in utero modifies long-term gene expression and the nature of interactions between the genotype and postnatal environment (16). Epidemiological studies show that, in humans, impaired growth in fetal life, followed by rapid catch-up growth in infancy, is a risk factor for non-insulindependent diabetes and cardiovascular disease (5, 6). Such findings suggest that, while the origins of the metabolic syndrome in humans are complex and multifactorial, nutrition in early life may be a contributing factor. The etiology of all of the main components of the syndrome (obesity, hyperinsulinemia, dyslipidemia, and cardiovascular and renal disease) is likely to involve a variety of influences across the lifespan (9).The expression of genes that predispose to, or protect against, any of these conditions will be modified through interactions with the postnatal lifestyle and environment (16).Studies of rodents and sheep are consist...

Fetal undernutrition programmes risk of later metabolic disorders. Postnatal factors modify the programmed phenotype. This study aimed to assess the effects of a postnatal high-fat (HF) challenge on body weight gain, adiposity and gene expression following prenatal undernutrition. Pregnant rats were fed either a control diet or a low-protein (LP) diet, targeted at days 0 -7 (LPE), days 8 -14 (LPM), or days 15-22 (LPL) gestation. At 12 weeks of age offspring were either fed standard laboratory chow diet (4·13 % fat), or a 39·5 % fat diet, for 10 weeks. LP exposure had no effect on weight gain or abdominal fat in males. Females exposed to LP diet in utero exhibited a similar weight gain on HF diet as on the chow diet. Programming of fat deposition was noted in LPE females and males of the LPM and LPL groups (P¼ 0·019). Hypothalamic expression of galanin mRNA was similar in all groups, but expression of the galanin-2 receptor was modified by LP exposure in female offspring. Hepatic expression of sterol response element binding protein (SREBP-1c) was decreased by LP at both the mRNA (P¼ 0·008) and protein (P,0·001) level. HF feeding increased expression of SREBP-1c mRNA three-fold in controls, with little response noted in the LP groups. Interactions of factors such as postnatal diet, age and sex act together with prenatal factors to determine metabolic function and responsiveness at any stage of postnatal life. This study further establishes a role for prenatal nutrition in programming the genes involved in lipid metabolism and appetite regulation. The origins of the metabolic syndrome in humans are complex and multifactorial. The aetiology of all of the components of the syndrome (obesity, hyperinsulinaemia, dyslipidaemia, cardiovascular and renal disease) is likely to involve a variety of influences across the lifespan. The expression of genes that predispose to, or protect against any of these conditions will be modified through interactions with the postnatal lifestyle environment (diet, physical activity and smoking) 1 . It is also becoming clear that the environment encountered in fetal life modifies both gene expression and the nature of the gene -postnatal environment interaction 2,3 . Evidence for this prenatal component of disease risk comes from both epidemiological investigations and experimental studies in animals 4 . Studies with animals show clearly that undernutrition in pregnancy is able to programme raised blood pressure, glucose intolerance, insulin resistance and obesity 5 . Exposure to a low-protein (LP) diet in fetal life programmes a phenotype that resembles the metabolic syndrome in ageing rats 6,7 . In such animals the expression of transcription factors regulating lipogenesis, and their downstream target genes are noted to be suppressed until nine months of age. Over-expression in later adulthood occurs coincident with the appearance of metabolic disorders including hepatic steatosis 6,7 .The transcription factor, sterol response element binding protein (SREBP)-1c, is one of the key regula...

Prenatal exposure to a low-protein diet programmes altered expression of genes that regulate lipid metabolism, including SREBP-1c. The main aim of this study was to investigate whether programmed changes to hepatic SREBP-1c expression in the rat are glucocorticoid-dependent. Rats were fed isocaloric diets (control or low-protein) throughout pregnancy. The low-protein group received 11beta-hydroxylase inhibitor, the inhibitor plus corticosterone, or vehicle injections over the first 2 weeks of pregnancy. The control group was administered vehicle injections only. On delivery the animals were transferred to a standard chow diet. The offspring were weaned at 4 weeks of age on to the same chow diet and killed for collection of liver tissue. The inhibitor of glucocorticoid synthesis reversed the suppressive effect of low-protein diet on hepatic SREBP-1c expression of both protein and mRNA seen in low-protein exposed offspring. To test if this effect is through direct effect on the SREBP-1c promoter, H4IIE cells were transfected with a luciferase reporter construct controlled by the SREBP-1c promoter treated with dexamethasone. Dexamethasone induced the expression of SREBP-1c in vitro. Together these studies demonstrate that foetal over-exposure to glucocorticoids, through indirect mechanism, play a crucial role in low-protein-diet-induced changes in lipid metabolism regulating genes.

The Hypothalamic – Pituitary – Adrenal (HPA) Axis is a unique system that mediates an immediate reactivity to a wide range of stimuli. It has a crucial role in synchronizing the behavioral and hormonal responses to internal and external threats, therefore, increases the chance of survival. It also enables the body systems to adapt to challenges put up by the pregnancy. Since the early stages of pregnancy and throughout delivery, HPA axis of the mother continuously navigates that of the fetus, and both have a specific cross talk even beyond the point of delivery and during postnatal period. Any disturbance in the interaction between the maternal and fetal HPA axes can adversely affect both. The HPA axis is argued to be the mechanism through which maternal stress and other suboptimal conditions during prenatal period can program the fetus for chronic disease in later life. In this chapter, the physiological and non-physiological communications between maternal and fetal HPA axes will be addressed while highlighting specific and unique aspects of this pathway.

No abstract