BIESWAL, FLORENCE, MARIE-THÉ RÈ SE AHN, BRIGITTE REUSENS, PAUL HOLVOET, MARTINE RAES, WILLIAM D. REES, AND CLAUDE REMACLE.The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. Obesity. 2006; 14:1330 -1343. Objective: To investigate whether catch-up growth after maternal malnutrition would favor the development of obesity in adulthood. Research Methods and Procedures: Pregnant rats were submitted to protein or calorie restriction during the course of gestation. During lactation, pups were protein-restricted, normally fed, or overfed [reduced litter size, control (C) diet]. At weaning, rats were transferred to chow or to a hypercaloric diet (HCD) known to induce obesity. Body weight, food intake, blood parameters, glucose tolerance, adipocyte cellularity, and adipose factors contributing to cardiovascular disease development were measured. Results: Protein and calorie restriction during gestation led to growth retardation at birth. If malnutrition was prolonged throughout lactation, adult body weight was permanently reduced. However, growth-retarded offspring overfed during the suckling period underwent a rapid catch-up growth and became heavier than the normally fed Cs. Offspring of calorie-restricted rats gained more weight than those of dams fed protein-restricted diet. Feeding an HCD postnatally amplified the effect of calorie restriction, and offspring that underwent catch-up growth became more obese than Cs. The HCD was associated with hyperphagia, hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance, and adipocyte hypertrophy. The magnitude of effects varied depending on the type and the timing of early malnutrition. The expression of genes encoding factors implicated in cardiovascular disease was also modulated differently by early malnutrition and adult obesity. Discussion: Catch-up growth immediately after early malnutrition should be a key point for the programming of obesity.

BACKGROUND: There is evidence that malnutrition in early life induces a growth retardation leading, in adult life, to manifest components of the metabolic syndrome. However, the impact on obesity seems less clearly established. OBJECTIVE: To review the effects of foetal and postnatal malnutrition on the programming of obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases. METHODS: Included in the review were recent papers exploring the mechanisms linking maternal nutrition with impaired foetal growth and later obesity, cardiovascular disease, hypertension and diabetes in humans and animals. RESULTS: The programming of obesity during foetal and early postnatal life depends of the timing of maternal malnutrition as well as the postnatal environment. Obesity arises principally in offspring submitted to malnutrition during early stages of gestation and which presented early catch-up growth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favourable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis). Adipose tissue secretes actively several factors implicated in inflammation, blood pressure, coagulation and fibrinolysis. The programmed development of intra-abdominal obesity after early growth restriction may thus favour higher prevalence of hypertension and cardiovascular diseases. CONCLUSIONS: Abdominal obesity appears in malnourished offspring and is aggravated by early catch-up growth. Higher rates of intra-abdominal obesity observed after growth restriction may participate to hypertension and create atherothrombotic conditions leading to the development of cardiovascular diseases.

Studies on fetal undernutrition have generated the hypothesis that fetal programming corresponds to an attempt of the fetus to adapt to adverse conditions encountered in utero. These adaptations would be beneficial if these conditions prevail later in life, but they become detrimental in the case of normal or plentiful nutrition and favor the appearance of the metabolic syndrome. In this article, the discussion is limited to the developmental programming of obesity and cardiovascular disorders caused by an early mismatched nutrition, particularly intrauterine growth retardation followed by postnatal catch-up growth. Selected data in humans are reviewed before evoking some mechanisms revealed or suggested by experiments in rodents. A variety of physiologic mechanisms are implicated in obesity programming, 2 of which are detailed. In some, but not all observations, hyperphagia resulting namely from perturbed development of the hypothalamic circuitry devoted to appetite regulation may contribute to obesity. Another contribution may be the developmental changes in the population of fat cell precursors in adipose tissue. Even if the link between obesity and cardiovascular disease is well established, alteration of blood pressure regulation may appear independently of obesity. A loss of diurnal variation in heart rate and blood pressure in adulthood has resulted from maternal undernutrition followed by postnatal overnutrition. Further research should clarify the effect of mismatched early nutrition on the development of brain centers regulating energy intake, energy expenditure, and circadian rhythms.

Poor development in utero may favor the development of obesity in adulthood. Animal studies showed that embryo manipulation in vitro or nutritional insults during the embryonic and fetal stages of development may lead to obesity in adult life. We studied the in vitro proliferation and differentiation of adipocytes to investigate whether early protein restriction may program cell growth and development. In a series of experiments, 2 different low-protein diet protocols were compared. In both cases, pregnant rats were fed a diet with a high (18-20%) or low (8-9%) protein content during gestation and/or lactation. Preadipocytes were isolated from the fetuses, neonates, and weanling offspring. Moderate protein restriction, imposed during either gestation and/or lactation, did not affect the capacity of preadipose cells to divide or store fat. Because previous studies showed that early protein restriction alters the metabolism of sulfur amino acids, we also investigated the effects of methionine, taurine, and homocysteine on proliferation and differentiation of preadipocytes. The supplementation of the diet with methionine or the addition of homocysteine and taurine to the culture media did not influence the development of preadipocytes. We obtained no evidence for the direct reprogramming of the precursor or stem cells and suggest that the subsequent alteration in fat accretion may therefore reflect a change in the neuroendocrine environment.