Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat

Abstract

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...

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“…Fatty liver can ultimately lead to inflammation and scarring (Erhuma et al 2007). Although this condition has multiple causes, fatty liver is a pathological condition in which triglyceride fats accumulate within hepatocytes.…”

Perinatal nutrient restriction induces long-lasting alterations in the circadian expression pattern of genes regulating food intake and energy metabolism

“…Many epidemiological studies have indeed demonstrated that infants born small for gestational age are more prone to develop obesity, hypertension and type 2 diabetes in adulthood. [27][28][29] Experimental studies have further corroborated that rodents and other animal species submitted to protein or calorie restriction during gestation and/or suckling exhibit hyperphagia, [30][31][32][33] insulin resistance, 34,35 reduced leptin sensitivity, 36,37 hepatic steatosis, 38 elevated blood pressure 39,40 and hyperlipidemia. 35,37,38 These observations have been explained by the thrifty phenotype hypothesis, also called metabolic programming or the developmental origins of disease.…”

“…[27][28][29] Experimental studies have further corroborated that rodents and other animal species submitted to protein or calorie restriction during gestation and/or suckling exhibit hyperphagia, [30][31][32][33] insulin resistance, 34,35 reduced leptin sensitivity, 36,37 hepatic steatosis, 38 elevated blood pressure 39,40 and hyperlipidemia. 35,37,38 These observations have been explained by the thrifty phenotype hypothesis, also called metabolic programming or the developmental origins of disease. [41][42][43][44][45] It is hypothesized that perinatal undernutrition sensitizes the offspring to the development of metabolic diseases via epigenetic changes that act during early life to program feeding behavior and energy homeostasis for optimal survival under nutritionallydeficient conditions.…”

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