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...

The evidence that omega-3 (n-3) and -6 (n-6) polyunsaturated fatty acids (PUFAs) have differential effects on ovarian function, oocytes and embryo quality is inconsistent. We report on the effects of n-3 versus n-6 PUFA-enriched diets fed to 36 ewes over a 6-week period, prior to ovarian stimulation and follicular aspiration, on ovarian steroidogenic parameters and embryo quality. Follicle number and size were unaltered by diet, but follicular-fluid progesterone concentrations were greater in n-3 PUFA-fed ewes than in n-6 PUFA-fed ewes. The percentage of saturated FAs (mostly stearic acid) was greater in oocytes than in either granulosa cells or plasma, indicating selective uptake and/or de novo synthesis of saturated FAs at the expense of PUFAs by oocytes. High-density lipoproteins (HDLs) fractionated from sera of these ewes increased granulosa cell proliferation and steroidogenesis relative to the FA-free BSA control during culture, but there was no differential effect of n-3 and n-6 PUFAs on either oestradiol or progesterone production. HDL was ineffective in delivering FAs to embryos during culture, although n-6 PUFA HDL reduced embryo development. All blastocysts, irrespective of the treatment, contained high levels of unsaturated FAs, in particular linoleic acid. Transcripts for HDL and low-density lipoprotein (LDL) receptors (SCARB1 and LDLR) and stearoyl-CoA desaturase (SCD) are reported in sheep embryos. HDL reduced the expression of transcripts for LDLR and SCD relative to the BSA control. The data support a differential effect of n-3 and n-6 PUFAs on ovarian steroidogenesis and pre-implantation development, the latter in the absence of a net uptake of FAs.

In 1991, the Committee on Medical Aspects of Food Policy produced a report on the dietary reference values for food energy and nutrients for groups of people in the United Kingdom. The resulting recommendations, which included specific limits for intakes of total, saturated, trans-and cis-polyunsaturated fatty acids (PUFA) have remained a cornerstone of public health policy ever since, and similar recommendations have been adopted by the World Health Organization. These recommendations were made largely on the basis of specific effects of these fatty acids on the risk of developing atherosclerotic cardiovascular disease (CVD). The intervening years have seen a plethora of human epidemiological and intervention trials to further elucidate the specific relationship between dietary fatty acid intake, plasma lipids and lipoproteins and cardiovascular morbidity and mortality. A number of recent meta-analyses and systematic reviews have revisited the role of specific dietary fatty acid classes and CVD risk. In general, these continue to support a link between saturated fatty acids (SFA) and CVD morbidity/mortality. They also highlight the potent adverse effects of trans fatty acids derived from partially hydrogenated vegetable oil. The most recent data suggest that replacing SFA with cis-PUFA (primarily linoleic acid) has the greatest impact on reducing CVD risk. Evidence of specific beneficial effects of n-3 PUFA is generally stronger for secondary, rather than primary, CVD risk, and it is restricted to very long chain fatty acids of marine origin as opposed to alpha-linolenic acid. Taken together, these data suggest that recent focus on dietary n-6-to-n-3 PUFA ratios may have been misguided, and that future strategies should focus on replacing dietary SFA with total PUFA, rather than concentrating on n-6 : n-3 PUFA ratio.

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Diets rich in saturated fatty acids have long been associated with increased plasma cholesterol concentrations and hence increased risk of cardiovascular disease. More recently, they have also been suggested to promote the development of non-alcoholic fatty liver disease. While there is now considerable evidence to suggest that polyunsaturated fatty acids exert many of their effects through regulating the activity of transcription factors, including peroxisome proliferator activated receptors, sterol regulatory binding proteins (SREBPs) and liver X receptor, our understanding of how saturated fatty acids act is still limited. Here we review the potential mechanisms whereby saturated fatty acids modulate hepatic lipid metabolism thereby impacting on the synthesis, storage and secretion of lipids. Evidence is presented that their effects are, at least partly, mediated through modulation of the activity of the SREBP family of transcription factors.

While it is well established that the fatty acid composition of dietary fat is important in determining plasma lipoprotein cholesterol concentrations, the effects of changing the absolute quantities of the individual fatty acids are less clear. In the present study Golden Syrian hamsters were fed on isoenergetic, low cholesterol (0.05 g/kg) diets containing 100, 150 or 200 g added fat/kg. This consisted of triolein (TO) alone, or equal proportions of TO and either trimyristin (TM), tripalmitin (TP) or tristearin (TS). Each trial also included a control group fed on a diet containing 50g TO/kg. As the mass of TO in the diet increased, plasma VLDL-cholesterol concentrations rose. The Th4-rich diets produced a concentration-dependent increase in total plasma cholesterol which was a result of significant increases in both VLDL and HDL levels. The TP-rich diets increased plasma LDL-and HDL-cholesterol levels in a concentrationdependent manner. TS-containing diets did not increase the cholesterol content of any of the major lipoprotein fractions. Hepatic LDL-receptor mRNA concentrations were significantly decreased in animals fed on TP, while apolipoprotein B mRNA concentrations were significantly increased. Thus, on a low-cholesterol diet, increasing the absolute amount of dietary palmitic acid increases LDL-cholesterol more than either myristic or stearic acid. These effects on lipoprotein metabolism may be exerted through specific modulation of the expression of the LDL receptor and apolipoprotein B genes.

Poor quality of nutrition during fetal development is associated with adverse health outcomes in adult life. Epidemiological studies suggest that markers of fetal undernutrition are predictive of risk of the metabolic syndrome and CHD. Here we show that feeding a low-protein diet during pregnancy programmed the development of atherosclerosis in ApoE*3-Leiden mice. ApoE*3-Leiden mice carry a mutation of human ApoE*3 rendering them prone to atherosclerosis when fed a diet rich in cholesterol. It was noted that fetal exposure to protein restriction led to a greater degree of dyslipidaemia in mice when fed an atherogenic diet, with low-protein-exposed ApoE*3 mice having elevated total plasma cholesterol (34 % higher; P < 0.001) and TAG (39 % higher; P < 0.001) relative to offspring exposed to a control diet in utero. The low-protein group developed more severe atherosclerotic lesions within the aortic arch (2.61-fold greater lesion area; P < 0.001). Analysis of a targeted gene array suggested a potential role for members of the LDL receptor superfamily, along with similar programmed suppression of the mRNA expression of hepatic sterol regulatory element-binding protein-1c. This indicates that disordered lipid metabolism may play a role in the fetal programming of atherosclerosis in this model. Whereas earlier studies have shown early programming of cardiovascular risk factors, these results demonstrate for the first time that the interaction of prenatal undernutrition with a postnatal atherogenic diet increases the extent of atherosclerotic disease.