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Laboratory of Cell Biology, 1348 Louvain-la-Neuve, Belgium and * The Rowett Research Institute, Bucksburn, Aberdeen, AB21 9SB, Scotland
2To whom correspondence should be addressed. E-mail: remacle{at}bani.ucl.ac.be.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • fetal programming • low-protein diet • preadipocytes • obesity
There is increasing evidence that poor nutrition in early life has long-term effects on adult health; poor intrauterine growth is associated with impaired glucose tolerance and an increased risk of developing noninsulin-dependent diabetes mellitus, hypertension, and cardiovascular diseases (1). There is also evidence to suggest that the fetal environment may predispose an individual to the development of obesity as an adult. Epidemiologic studies showed that children with a low birth weight tend to develop insulin resistance and central obesity as early as 8 y of age (2,3). Studies of humans exposed to famine during gestation suggest that the early stages of development are particularly important because individuals whose mothers were malnourished early in pregnancy had a higher rate of intra-abdominal obesity than those whose mothers were underfed during the later stages (4). Because intra-abdominal obesity increases the risk of cardiovascular diseases and type-2 diabetes independently of the appearance of generalized obesity, prenatal programming of visceral adipose development may be particularly important in the progression of metabolic disease.
The mechanism by which early nutritional insults modify the development of the adipocyte and its metabolism is still unclear. One possible explanation is that the early stem and precursor cells of the embryo are sensitive to their environment and that this early event leads to persistent changes in the resulting tissues. For example, cloned mice have an obese phenotype, which appears to be the result of aberrant epigenetic reprogramming during the nuclear transfer procedure (5). It is hypothesized, in this model, that adult onset obesity results from programming of the stem cells before they have developed into mature adipocytes. Such a mechanism would lead to changes in the growth and development of preadipose cells in culture and be apparent before the development of obesity in the adult offspring.
It is not clear whether nutritional insults can also modify the development of adipose tissue through the same mechanism that leads to early programming by in vitro manipulation such as nuclear transfer. In a widely used animal model for the fetal origin of disease, pregnant rats are fed a low-protein diet. Fetuses of dams fed a low-protein diet during gestation present changes in the structure and function of their organs (6–10). Such alterations lead to perturbations in metabolism associated with insulin insensitivity and glucose intolerance at adult age (6,10). Part of this effect was due to changes in adipose tissue; adipocytes isolated from the 3-mo-old offspring of dams fed a reduced protein diet during gestation and lactation had increased basal and insulin-stimulated glucose uptake (11,12). Despite an increase in the expression of the insulin receptor, adipocytes from low-protein offspring have a selective resistance to the antilipolytic action of insulin (11,13,14). These modifications appear to be mediated by alterations in the expression and activities of various components of the insulin-signaling pathway (15,16).
Isolated stromal cells from adipose tissues provide a simple well-characterized tool for the analysis of fat cell proliferation and differentiation in vitro (17,18). To study the development of adipose tissue, we isolated cells from fetuses, neonates, and 1-mo-old offspring of rat dams fed either a complete or protein-restricted diet and examined the proliferation and development of preadipocyte cultures. The cells were induced to differentiate under identical metabolic and hormonal conditions in vitro to test for programming of the precursor cells. Despite the apparent simplicity of the protein restriction model, there are numerous subtle differences in the diets and protocols that are used in different laboratories (19). To consider as many of these variations as possible, 2 independent studies using 2 common formulations of protein-restricted diets were carried out in a parallel series of experiments. In Expt. 1, we studied preadipocytes from fetal, neonatal, and weanling offspring of rats fed either a control (18%) or a low-protein (9%) diet during gestation. These experiments also investigated the effect of different methionine contents in the low-protein diet. In Expt. 2, we studied the effect of protein malnutrition (8 vs. 20%) during gestation and lactation on the proliferation and differentiation of preadipocytes (subcutaneous, perirenal, and perigenital) isolated from weaned pups.
Previous studies showed that changes in plasma amino acid concentrations occur in animals fed a low-protein diet (20,21). In particular, a maternal low-protein diet perturbs methionine metabolism, reduces taurine supply, and increases homocysteine levels (22). To investigate whether changes in the concentration of these amino acids affect the proliferation and differentiation of preadipocytes, the low-protein diet was supplemented with methionine. We also analyzed the effect of adding taurine and homocysteine to the culture medium.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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230–240 g, the female rats were mated with males of the same strain. Mating was confirmed by detection of a vaginal plug and this was denoted d 0. The dams were fed the same diets throughout pregnancy. Dams were killed by concussion followed by cervical dislocation on d 21 of gestation and the tissues of fetuses were recovered. In subsequent experiments, the female rats were treated as described above except that the dams were kept until the end of gestation and pups were delivered naturally. On postnatal d 1, the litters were reduced to 8 pups. Once they had given birth, the dams consumed a nonpurified diet (CRM breeder diet Special Diet Services) ad libitum until weaning was complete. Subcutaneous cells were prepared from fetuses and from both male and female neonates (d 2) and weanlings (d 28) by scraping the ventral hypoderm (24). Samples of the cells were frozen in medium containing 10% (v:v) dimethylsulfoxide and 50% (v:v) fetal bovine serum (Gibco) and stored in liquid nitrogen until required. In Expt. 2, virgin female Wistar rats (Janvier) aged 3 mo were fed the HF diet containing 20 or 8% protein. The diets were fed from d 1 of gestation until the end of lactation. Spontaneous delivery took place at d 22 of pregnancy after which litters were reduced to 8 pups. At 21 d of age, all pups were weaned onto a stock diet. Male rats were killed by decapitation at the age of 4 wk.
Cell culture. In Expt. 1, fibroblastoid preadipocytes from rats of the Rowett Hooded Lister strain were isolated from subcutaneous tissues of fetuses, neonates, and weanlings (28 d of age) as described previously (24). Briefly, tissues were transferred in a buffer containing collagenase type II (1 g/L; Sigma) and digested for 1 h at 37°C in a shaking water bath. After incubation, the digest was filtered through sterile 250-µm nylon mesh and centrifuged at 250 x g for 10 min. The cell pellet was resuspended in Medium 199 (Gibco) supplemented with 10% fetal bovine serum, penicillin (100 kU/L), and streptomycin (100 mg/L) (Gibco). Cells derived from the neonates of a single dam were pooled and inoculated at a density of 1.5 x 108 cells/L into 96-well plates (Griener, Stonehouse). After 2 d in culture at 37°C in an atmosphere of 5% CO2, differentiation was induced by the addition of medium supplemented with isobutylmethylxanthine (0.5 mmol/L; Sigma), dexamethasone (0.25 µmol/L; Sigma) and insulin (10 g/L, CP Pharmaceuticals). After 48 h, the induction medium was removed and replaced by Medium 199 containing 10% (v:v) fetal bovine serum supplemented with insulin (10 mg/L) alone. This medium was changed every 2 d.
In Expt. 2, cells were prepared from rats of the Wistar strain. The stroma-vascular fractions from periepididymal, perirenal, and subcutaneous inguinal fat deposits were isolated as described previously (25) with some modifications. Tissues (1–3 g) were minced and digested with collagenase type II (5000 U/g tissue, Sigma) for 30 min at 37°C in a shaking water bath. The resulting cell suspension was filtered through a 200-µm mesh nylon filter and centrifuged at 400 x g for 5 min. The undissociated fragments remaining on the filter were incubated for another 15 min in collagenase, treated as above, and added to the first filtrate. The cells were resuspended in DMEM containing 4.5 g/L glucose supplemented with 10% (v:v) fetal bovine serum and antibiotics, inoculated into 6-well plates (Falcon 3046, Becton Dickinson) at a density of 7.5 x 107 cells/L, and maintained at 37°C in a 5% CO2 atmosphere. Perirenal and periepididymal preadipocytes were kept in DMEM containing the same components as the plating medium with the addition of 14.5 nmol/L insulin (Novo Nordisk) and 1 nmol/L dexamethasone (Sigma). A serum-free medium consisting of DME/HAM’S nutrient Mixture F12 (1:1; Gibco) supplemented with antibiotics, 14.5 nmol/L insulin, 1 nmol/L dexamethasone, 0.2 nmol/L 3,3',5-triiodo-L-thyronine (Sigma), 10 mg/L apo-transferrin (Sigma), 100 mmol/L L-ascorbic acid (Sigma), and 50 µmol/L 2-mercaptoethanol (Sigma) was used to study subcutaneous preadipocytes. The culture media were changed every 48 h. Preadipocytes were cultured for 6 d (subcutaneous cells) or 9 d (perirenal and periepididymal cells) after inoculation.
Assays for cell proliferation and differentiation. In Expt. 1, cell proliferation of preadipocytes was measured by adding an equal volume of 1% (v:v) glutaraldehyde in PBS to the medium, incubating at room temperature for 20 min, and then washing twice with 0.2 mL of PBS. The cells were stained with 1 g/L crystal violet, washed extensively, and the A630 of each well was read using a multiwell plate reader (26). In Expt. 2, the protein content was determined according to Bradford (27) as described previously (28). DNA was measured by fluorometry (excitation 372 nm, emission 454 nm) in a buffer containing 12 mmol/L NaCl, 5 mmol/L HEPES, 5 mmol/L EDTA, and 0.571 mmol/L diamidino-2-phenylindole (Sigma). Calf thymus DNA (Boehringer) was used as a standard. Glycerol-3-phosphate dehydrogenase (GPDH; EC 1.1.1.8) activity was measured as described by Boone (28). Enzyme activity was expressed as µmol NADH degraded/(min · mg protein).
Lipid deposition. In Expt. 1, a duplicate set of cells was fixed with 1% (v:v) glutararaldehyde, stained with Oil Red O, washed extensively, and the A492 of each well was read using a multiwell plate reader (Labtech International). In Expt. 2, morphological quantifications were performed by calculating the proportion of undifferentiated cells and of scaled stages of progressing adipose conversion according to their lipid content and their nucleus position as previously described (25). The percentage of the 5 stages was calculated by counting a minimum of 500 cells/dish.
Effect of homocysteine and taurine on the proliferation and differentiation of stroma-vascular cells. An additional series of tests (Expt. 3) were performed to study the effect of sulfur amino acids on proliferation and differentiation of preadipocytes. Preadipocytes derived from the neonates of Rowett Hooded Lister dams fed a stock diet were isolated and inoculated as described above for Expt. 1. Cells were exposed to a range of homocysteine concentrations covering the expected physiologic range (0, 1, 5, 10, 25, 50, 100, 250, 500, 750, and 1000 µmol/L). The homocysteine was added on d 1 and remained in the culture medium until the cells were harvested 48 h later. Perirenal and periepididymal preadipocytes from 4-wk-old offspring of Wistar dams fed a stock diet were exposed to physiologic (0.3 mmol/L) or supraphysiologic (3 mmol/L) concentrations of taurine. Cells were treated as described for Expt. 2 except that taurine was present in the media from d 1. The capacity for proliferation and differentiation was determined.
Statistical analysis. Experimental results are reported as means ± SEM. Data were analyzed by one-way ANOVA followed by a Tukey multiple comparison test. Data were processed using the Prism Software (GraphPad Software). Differences with a P-value of <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In this experiment, the dams were returned to stock diets once they had given birth. Because they were not fed the reduced protein diet during lactation, there was no difference in the weight of the offspring at 19 d of age when they were weaned. The offspring of dams fed diets containing 18% protein weighed 40.4 ± 2.6 g; the offspring of those fed 9% protein supplemented with 0.1 or 0.4% methionine weighed 41.3 ± 3.8 g and 39.5 ± 3.5 g, respectively.
The maternal diet did not affect cell proliferation or fat accumulation in cultures of subcutaneous preadipocytes derived from fetuses, neonates, and weanling pups (Table 2). Approximately 8–10% of the cells in cultures of preadipocytes prepared from fetal and neonatal offspring contained fat droplets which stained with Oil Red O. The number of cells containing fat was related to the number of cells seeded into the well, and microscopic examination did not suggest that there were gross differences in the morphology of cells from the different dietary treatments. This suggests that neither the early protein restriction nor the diet formula affected cell proliferation and fat accumulation regardless of the developmental stage.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Our previous studies showed that the low-protein diet interferes with the maternal and fetal serum profile of amino acids (20,21). In particular, the changes in protein content of the diet affect the metabolism of sulfur amino acids. The semisynthetic diets use casein, which has a low cysteine content, as the protein source. This forces the animal to synthesize a large part of its cysteine and taurine requirement from methionine (22,29). Although there is evidence to suggest that subtle differences in methionine content in the diet may be of major importance to elicit the programming of hypertension in rats (19), our data do not suggest that it is important in adipocyte development. When the diet is low in protein, the oxidation of amino acids is reduced, perturbing methionine metabolism and inducing a reduction in taurine supply and an increase in homocysteine levels. Taurine and homocysteine are important for fetal growth (30,31). Recent studies showed that taurine supplementation of the low-protein diet restores most of the alterations induced in the endocrine pancreas (32–34). A change in the serum concentrations of these amino acids is associated with diseases in adults. An excess of homocysteine is associated with increased risk of cardiovascular disease (35,36), whereas taurine has hypocholesterolemic and antiatherosclerotic effects (37,38) and seems to improve insulin sensitivity (39,40). Our present data suggest that these compounds do not affect preadipocyte proliferation and differentiation when they are added to the culture media in vitro, suggesting that there is no direct effect on adipocyte development.
The present data suggest that the prenatal programming of adipose development is not the consequence of a direct effect on the cells but is more likely to result from a change in appetite control or the hormonal environment, leading to a secondary change in the development of adipose tissue. Of particular interest are the changes in the glucocorticoid and insulin axes in the offspring of malnourished rats. Elevated circulating levels of glucocorticoids or hypersensitivity to these hormones has long been thought to play a role in the development and maintenance of obesity and insulin resistance (41,42). In rats, undernutrition during late gestation exposes the fetuses to maternal glucocorticoids, leading to growth retardation at birth (43,44) and to permanent hyperactivity of the hypothalamo-pituitary-adrenal axis (HPA axis) associated with a hypersecretion of corticosterone in adulthood (45). In addition, overexposure to glucocorticoids in early life was suggested to program hypertension, glucose intolerance, and hyperinsulinemia in adult rats (46–48). Therefore, dysregulation of the HPA axis induced by early protein malnutrition may play a key role in the altered metabolism of adipocytes and favor the development of obesity. The predisposition toward obesity may also result from alterations in the insulin axis. Previous studies showed that feeding dams a low-protein diet reduces the proliferation and insulin content of fetal pancreatic islet cells (6). These alterations persist into adult life and are reflected by a decrease in ß-cell number and impaired insulin secretion (7). The underdevelopment of the endocrine pancreas as a response to malnutrition may be a survival advantage in early life when there is poor or cyclic availability of food. However, it may be detrimental for health later in life because under more favorable nutritional conditions, this could contribute to greater obesity.
Protein deficiency during perinatal life significantly decreases fetal growth and may lead to intra-abdominal obesity in adulthood. Adipocytes of early growth-restricted rats present long-term changes in insulin signaling and fat storage. However, we contend that the changes in adiposity observed in the offspring of dams fed the low-protein diet during gestation do not result from a direct effect of nutrient deficiency on the adipocyte lineage but rather are a consequence of the altered hormonal environment.
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FOOTNOTES |
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3 Abbreviations used: GPDH, glycerol phosphate dehydrogenase (EC 1.1.1.8); HF diet, Hope Farm diet; HPA axis, hypothalamo-pituitary-adrenal axis; UoS diet, University of Southampton diet.
Manuscript received 22 December 2003. Initial review completed 21 January 2004. Revision accepted 31 March 2004.
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