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2
*
Department Biochemistry and Physiology of Nutrition, Deutsches Institut für Ernährungsforschung (DIfE) (German Institute of Human Nutrition), 14558 Bergholz-Rehbrücke, Germany and
Research Unit Nutritional Physiology "Oskar Kellner," Forschungsinstitut für die Biologie landwirtschaftlicher Nutztiere (Research Institute for the Biology of Farm Animals), 18196 Dummerstorf, Germany
2To whom correspondence should be addressed. E-mail: metges{at}fbn-dummerstorf.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • nutritional programming • fetal development • amino acids • obesity • dietary high protein • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). In addition, numerous rodent studies have shown that maternal low protein intake can result in low birth weight and subsequently lead to various metabolic disturbances in adulthood such as high blood pressure, impaired glucose tolerance and insulin resistance. This phenomenon has been termed "nutritional programming" (2
). By contrast, earlier observational studies in pregnant women suggest that a high protein density (>20% of total energy intake) is related to a lower birth weight of their infants, whereas more recent studies are inconclusive (3
–5
). Unfortunately, it is difficult to interpret these epidemiologic studies because many influential factors, such as dietary energy intake, had not been controlled. We therefore explored in a controlled rat experiment how a high level of protein in the maternal diet affects birth weight and adolescent body weight and fatness of the offspring. The second question we wished to address was whether pre- or postnatal protein nutrition is more influential in programming body weight, body fatness and energy expenditure in young rats. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The experiment was performed in accordance with the guidelines of the ethics committee of the Ministry of Agriculture, Nutrition and Forestry (State Brandenburg, Germany, Permission No. L48–3560-0/3). Rats were housed in a temperature-controlled room with 12-h light:dark cycle, and water was consumed ad libitum. Food consumption and body weight were monitored twice a week.
Female (
280 g body weight) and male (350 g body weight) adult rats (Shoe-Wistar; Tierzucht Schoenwalde, Schoenwalde, Germany) were switched from a commercial rat food (190 g/kg crude protein, 40 g/kg fat; Altromin GmbH, Lage, Germany) to purified, isoenergetic diets containing either a high protein (HP,3
400 g protein/kg;8 females) or an adequate protein concentration (AP; 200 g protein/kg; 9 females) (Table 1
). One male and one female rat each were housed together for 3 d to mate. During the gestation and lactation periods, dams were housed individually. The AP-group was always pair-fed based on the food intake of the HP-group throughout the experiment.
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Measurement of energy expenditure.
On d 60 or 61, energy expenditure of individual rats was measured using indirect calorimetry (6
). Oxygen consumption and CO2 production were determined every 6 min in an open respirometric system (O2 and CO2 analyzers: Magnos 16 and U14, Hartmann & Braun, Frankfurt/Main, Germany). Energy expenditure (EE) was calculated according to Weir (7
). Respiratory quotient (RQ) is carbon dioxide produced (VCO2) divided by oxygen consumed (VO2).
Total energy expenditure (TEE) was calculated as a 24-h mean. Resting metabolic rate (RMR) was calculated as a mean of the 20 lowest values during the measurement period according to a procedure previously described in mice (6
).
Measurement of body composition.
Anesthetized rats were killed by decapitation and blood samples were taken. Carcasses were weighed and stored frozen (-20°C) until body fat and lean body mass (LBM) were measured. Carcasses were autoclaved in 30 mL 5% HCl at 121°C for 3 h, homogenized and lyophilized. Lipid content of carcass was assayed by extraction with petroleum ether in a soxhlet extractor (8
,9
) and calculated as the difference between dry carcass weight before and after lipid extraction. LBM was calculated as carcass mass minus lipid mass.
Statistics.
Results are expressed as means ± SD. The effects of a high protein diet administered pre- and/or postnatally were evaluated by a two-way, one-interaction ANOVA (SPSS for Windows 8.0, SPSS 1998, Chicago,IL). When the interaction was significant, Scheffé’s post-hoc test was used for determination of significant differences among the four groups. Mean body weight on d 2 was analyzed by unpaired Students’ t test. A P-value of <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Litter sizes did not differ (HP: 8.9 ± 2.5; AP: 9.2 ± 3.1 pups).
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). Body weight gain during suckling was higher in the HP-AP group (36.2 g) than in the other groups (AP-AP: 25.3 g, AP-HP: 28.0 g, HP-HP: 25.4 g). Body weights in AP-HP and HP-AP groups continued to be higher until d 40 and there was a tendency for higher values until d 60 (P = 0.07), whereas HP-HP group showed the lowest body weight. There was a significant interaction of prenatal and postnatal protein exposure on body weight throughout the experiment (Table 2)
.
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Resting metabolic rate (RMR) was not influenced by dietary protein exposure, whereas total energy expenditure (TEE) was significantly affected by prenatal high protein exposure (P < 0.05, Table 2
). Prenatal high protein groups had a decreased total as well as weight-specific TEE. By contrast, postnatal protein level did not affect either TEE or RMR (Table 2)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,10
). However, when suckled by nurses fed an adequate protein level, HP-AP pups overcompensated in terms of catch-up growth until the end of the suckling period (Table 2)
. They displayed an almost fivefold increase in body mass during that period compared with all other groups (3-fold increase). However, rats that were continuously exposed to a high dietary protein environment remained lower in body weight and lean body mass than all other groups but had a tendency for greater body fat content, like the HP-AP group. This suggests that body fat, i.e., adiposity, was determined by prenatal protein exposure, whereas body weight per se was regulated by a complex interaction of pre- and postnatal protein level. However, our findings do not support observational reports in children and young adults that high protein feeding during early childhood alone leads to adiposity (11
–13
).
Although in humans a causal relationship between reduced energy expenditure and obesity is controversial (14
), many obese animal models are characterized by a reduced metabolic rate (6
,15
). Here we found that the prenatal protein level significantly affected TEE but not RMR. This might suggest that the programming effect on TEE is caused by influencing thermogenesis or physical activity rather than reprogramming metabolic parameters related to basal metabolic rate. This certainly warrants further investigation.
In contrast to our results with prenatal high protein feeding, others have shown that lifetime effects on body size were seen only in relation to postnatal low protein intake; thus animals reared by mothers fed a low protein diet during lactation were permanently smaller, whereas prenatal low protein diet fed to the mother had no long-term effect on the size of the offspring (16
). It appears, therefore, that there are distinctly different time-dependent programming effects due to high dietary protein intake.
Possible explanations for our findings might be linked to specific differences in maternal amino acid concentrations or hormones (e.g., insulin, thyroxin or insulin-like growth factor), which could trigger differences in fetal gene and protein expression of growth factor systems as discussed recently (1
,17
,18
).
In conclusion, we provide the first data suggesting that prenatal high protein exposure in rats can reprogram body weight, body fat content and energy expenditure in later life.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AP, adequate protein, HP, high protein, LBM, lean body mass, RMR, resting metabolic rate, RQ, respiratory quotient, TEE, total energy expenditure.
Manuscript received 1 August 2001. Revision accepted 12 November 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1.
Metges, C. C. (2001) Does dietary protein in early life affect the development of adiposity in mammals?. J. Nutr. 131:2062-2066.
2. Lucas, A. (1998) Programming by early nutrition: an experimental approach. J. Nutr. 128(suppl. 2):401S-406S.
3. Rush, D. (1989) Effect of changes in protein and calorie intake during pregnancy on the growth of the human fetus. Chalmers, I. Enkin, M. Kierse, M. J. eds. Effective Care in Pregnancy and Childbirth 1989:255-280 Oxford University Press Oxford, UK. .
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Mathews, F., Yudkin, P. & Neil, A. (1999) Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. Br. Med. J. 319:339-343.
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Godfrey, K., Robinson, S., Barker, D.J.P., Osmond, C. & Cox, V. (1996) Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. Br. Med. J. 312:410-414.
6.
Klaus, S., Münzberg, H., Trüloff, C. & Heldmaier, G. (1998) Physiology of transgenic mice with brown fat ablation: obesity is due to lowered body temperature. Am. J. Physiol. 274:R287-R293.
7. Weir, J. B. (1949) New methods for calculating metabolic rate with special reference to protein metabolism. J. Physiol. 109:1-9.
8. Association of Official Analytical Chemists (1990) Helnrich, K. eds. Official Methods of Analysis 15th ed. 1990 AOAC Arlington, VA .
9.
Proll, J., Petzke, K. K., Ezeagu, I. E. & Metges, C. C. (1998) Low nutritional quality of unconventional tropical crop seeds in rats. J. Nutr. 128:2014-2022.
10. Holness, M. J., Langdown, M. L. & Sugden, M. C. (2000) Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus. Biochem. J. 349:657-665.
11. Rolland-Cachera, M. F., Deheeger, M., Akrout, M. & Bellisle, F. (1995) Influence of macronutrients on adiposity development: a follow up study of nutrition and growth from 10 months to 8 years of age. Int. J. Obes. Relat. Metab. Disord. 19:573-578.[Medline]
12. Kemper, H. C., Post, G. B., Twisk, J. W. & van Mechelen, W. (1999) Lifestyle and obesity in adolescence and young adulthood: results from the Amsterdam Growth and Health Longitudinal Study (AGAHLS). Int. J. Obes. Relat. Metab. Disord. 23(suppl. 3):S34-S40.
13. Scaglioni, S., Agostoni, C., Notaris, R. D., Radaelli, G., Radice, N., Valenti, M., Giovannini, M. & Riva, E. (2000) Early macronutrient intake and overweight at five years of age. Int. J. Obes. Relat. Metab. Disord. 24:777-781.[Medline]
14. Goran, M. I. (2000) Energy metabolism and obesity. Med. Clin. N. Am. 84:347-362.[Medline]
15. Robinson, S. W., Dinulescu, D. M. & Cone, R. D. (2000) Genetic models of obesity and energy imbalance in the mouse. Annu. Rev. Genet. 34:687-745.[Medline]
16. Desai, M., Crowther, N.K.J., Lucas, A. & Hales, C. N. (1996) Organ-selective growth in the offspring of protein-restricted mothers. Br. J. Nutr. 76:591-603.[Medline]
17. Fafournoux, P., Bruhat, A. & Jousse, C. (2000) Amino acid regulation of gene expression. Biochem. J. 351:1-12.[Medline]
18. Simmen, F. A., Badinga, L., Green, M. L., Kwak, I., Song, S. & Simmen, R.C.M. (1998) The porcine insulin-like growth factor system: at the interface of nutrition, growth, and reproduction. J. Nutr. 128:315S-320S.
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