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Articles

Does Dietary Protein in Early Life Affect the Development of Adiposity in Mammals?

Deutsches Institut für Ernährungsforschung, D-14558, Bergholz-Rehbrücke, Germany

¹To whom correspondence should be addressed. E-mail: metges{at}www.dife.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION Effects of prenatal dietary... Effects of high dietary... REFERENCES

 
This article examines the proposition that dietary protein in pre- and early postnatal life influences the development of adiposity in later life. In rodents, low protein intake during gestation can result in low birth weight and subsequently leads to various metabolic disturbances in adulthood, such as high blood pressure, impaired glucose tolerance and insulin resistance. The few controlled studies conducted in animals suggest that high protein or energy intake during gestation leads to low birth weights. Observational studies in humans have been inconclusive in establishing a relationship between dietary protein intake in pregnancy and effects on birth weight and adiposity of the offspring later in life. There is only weak epidemiological evidence linking high protein intake during early childhood and the development of obesity. By contrast, studies in domestic animals have found that higher levels of protein intake are often associated with lower rates of fat accretion. Additional studies are proposed to explore claims linking protein nutrition in early life to the postnatal development of obesity and disease in humans.

KEY WORDS: • fetal programming • amino acid homeostasis • breast-feeding • growth velocity

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Effects of prenatal dietary... Effects of high dietary... REFERENCES

 
The phenomenon of nutrition in early life having lifetime effects on growth, metabolism and health has been termed "nutritional programming" and has been defined as a long-term change in the structure or function of an organism resulting from a stimulus acting at a critical period of development in early life (1) . It has been proposed that poor intrauterine growth not only contributes to increased morbidity and mortality during infancy, but also that it has the potential to compromise adult health and well being. Over the past decade, epidemiological studies in several countries have shown that size at birth and/or placental weight is related to adult health and disease (2 3 4) , but the association between low birth weight and greater risk of fatness has not been observed in all studies (5) . That maternal or fetal nutrition has the potential to cause adverse fetal growth and long-term health problems has been met with much skepticism. An additional issue in this context is nutrition in infancy (pre- and postweaning) and its importance in the manifestation of obesity in later life. Major reasons for this skepticism are that the findings are primarily based on epidemiological evidence relating events several decades apart, with no information on the intervening period and adjustment of confounding variables such as adult body size (6 7 8 9) . The purpose of this article is to summarize current information on the relationship between maternal dietary protein intake and birth weight in the offspring and protein intake in early postnatal life and body fatness before and after puberty. Research strategies are proposed that may help to resolve the complex issues and debates surrounding this important area of early nutrition, and, finally, to establish the biological mechanisms underpinning the relationships between growth regulation and disease prevention and the role of nutrient intake in the life cycle.

	Effects of prenatal dietary protein exposure on birth weight in later life

TOP ABSTRACT INTRODUCTION Effects of prenatal dietary... Effects of high dietary... REFERENCES

 
Results from rodent studies suggest that low protein intake during gestation (i.e., 80–100 g protein/kg diet vs. 200 g protein/kg diet) can result in low birth weight or thinness at birth and, subsequently, the development of metabolic disturbances in adult life, such as high blood pressure, impaired glucose tolerance and insulin resistance (10) . By contrast, there is some evidence, albeit limited, that high protein or energy intake during gestation can lead to reduced birth weight (11 12 13) . Indeed, overnutrition in adolescent sheep throughout pregnancy results in a major restriction in placental mass and a significant reduction in birth weight relative to moderately fed adolescents of equivalent gynecological age (14) . Whether the same or different mechanisms occur during human fetal development has not been resolved.

Epidemiological investigations have recently examined whether low protein intake during pregnancy might be a risk factor for women to give birth to small infants or to have children with metabolic disturbances in later life. Godfrey et al. (15) reported that low protein intake in late pregnancy was associated with lower placental and birth weights, whereas a prospective study by Mathews et al. (16) failed to establish a relationship between macronutrient intake and birth weight. In that study, vitamin C was the only nutrient predictive of changes in placental and birth weights. Interestingly, both studies identified higher birth weights when protein intake was lowest in early pregnancy (15 ,16 ; Fig. 1 ). There is insufficient evidence that the intake of isocaloric protein supplements during pregnancy may result in a decrease or an insignificant increase in maternal weight gain, a decreased mean birth weight and an increased risk of small for gestational age births (17 ,18) .

View larger version (29K): [in this window] [in a new window]   Figure 1. Relationship between daily dietary protein intakes in pregnant women and birth weight of their infants in two recent studies; empty bars (16) ; filled bars (15) . Values are medians.

Studies in animals have now begun to indicate that there is a window during gestation when the fetus is most susceptible to maternal protein deficiency. Low protein intake by rat dams during the preimplantation period only, with dams fed an adequate control diet for the remainder of gestation, results in a reprogramming of birth weight and postnatal growth rate and the development of hypertension (24) . Conversely, in humans, improving the nutritional status during the prepregnancy period resulted in higher birth weights and length, but it is not known which of the various nutrients are involved (25) . Studies in pregnant women suggest that pregnancy-related adaptation in maternal nitrogen metabolism occurs in the first trimester, before any significant change in fetal nitrogen accretion (26) . The earliest recorded nutritional information in the human studies by Mathews et al. (16) was a median of 16.3 wk and for the study by Godfrey et al. (15) was a median of 15.3 wk. Currently it is unclear how relevant these selected time points are for the outcomes studied.

	Effects of high dietary protein intake during early childhood on development of later adiposity

TOP ABSTRACT INTRODUCTION Effects of prenatal dietary... Effects of high dietary... REFERENCES

 
In growing rats, body fat accumulation was directly linked to the protein content of the diet, inversely proportional to the fat level and not related to the carbohydrate content (27) . By contrast, in growing pigs increasing protein intake usually results in a decrease in fat accretion (28 ,29) . In a longitudinal study in children, protein intake at an early age was found to affect the development of fatness later in life. Here, a positive correlation was observed between protein (% of energy) intake at the age of 2 y and body mass index (weight in kg/height in m²) and subscapular skinfold at 8 y (30) . Scagliono et al. (21) also found that 5-y-old overweight children had a significantly higher percentage intake of protein (22% vs. 20%) at 1 y of age than did nonoverweight children. A positive relation between protein intake and body fat mass was also found in a longitudinal study in adolescents and young adults (31) . The odds ratio for dietary protein intake and body fat mass was 1.5, while energy intake was negatively related to body fat (odds ratio: 0.37; 31). A common weakness of these studies is that obesity is related to protein as the percentage of energy and not as grams of protein intake per day. Furthermore, energy intake estimated from food frequency questionnaires or dietary recall methods are frequently underreported (32) . Therefore, it cannot be excluded that the true protein intakes of these children were overestimated. Furthermore, because parental overweightness is a major risk factor for childhood overweightness and increased adult body weight, it would have been prudent to control for this variable (21 ,33) . There is some evidence that birth weight and skinfold thickness (as a proxy for central adiposity) of children ages 5–11 y and young adults in the U. S. are inversely related (34 ,35) , further suggesting that fetal programming could be important in the development of obesity in childhood. Thus, it is important to know whether effects of protein intake in infancy on childhood obesity are modulated by differences in birth weight and, thus, by underlying effects of in utero nutritional environment. Nevertheless, dietary protein intake in children is much higher than recommended. For example, results of the German Nationale Verzehrsstudie (National Dietary Survey) indicate that in German boys and girls ages 4–10 y mean protein intake is 3 times the recommended levels, and 1.5–2 times the recommended levels for children up to 14 y old (36) . This is also the case for protein intake in children and adolescents in other European countries (37 ,38) . The extent of the excess protein intake and the inherently different growth velocities of humans versus other mammalian species might explain discrepancies between studies in growing domestic animals and children.

Plasma amino acid and blood urea concentrations have been used to assess the adequacy of protein intake and dietary amino acid patterns of formula-fed infants. The plasma amino acid pattern of the breast-fed infant is assumed to be the gold standard for this comparison. Mature milk (> 10 d postpartum) contains between 8 and 12 g/L true protein (39 ,40) or 1.6 ± 0.19 g protein/0.42 MJ (100 kcal; 41 ). Although it is practically impossible to produce a formula that matches exactly the amino acid pattern and absorption kinetics of human milk protein, studies indicate that feeding formulas (13 g/L true protein) containing predominantly whey as the protein source results in a plasma aminogram that is similar to that of breast-fed infants (42 ,43) .

Infants receiving formula food consume 66%–70% more protein compared with breast-fed infants (44) . This fact may explain why breast-fed infants are leaner than are formula-fed infants at 1 y of age (45) . However, it cannot be excluded that differences in energy intake or other confounding factors play a role in the development of adiposity in infants (5 ,44 ,45) . By contrast, a longitudinal investigation in children did not indicate that total energy intake at 12 wk of age is a major determinant of body fatness at 2–3.5 y (46) . Infants ages 8 to 111 d old and fed a formula with a protein:energy ratio of 5.11 g/MJ (2.13 g/100 kcal) showed similar gain in length but a tendency for higher body weight gains than those observed in a formula-fed group receiving 3.73–2.99 g/MJ (1.56–1.25 g/100 kcal) (47) . Body mass index was significantly higher in infants fed a formula containing 4 g/MJ (1.7 g/100 kcal) compared with a breast-fed reference group, suggesting more fat accumulation in infants fed this formula (48) . Infants 4–6 mo of age had a significantly higher body weight gain when receiving a formula containing 18 g protein/L compared with an isocaloric formula containing 13 g protein/L; body fat mass was not reported (49) . In a recent German study, an inverse relationship between duration of breast-feeding and the prevalence of being overweight or obese at 5–6 y of age was observed (50) . In children who had been breast-fed for at least 6 mo or more and very likely consumed less protein than those who had been formula fed, the risk of being overweight or obese were reduced by > 30% and > 40%, respectively (50) . Similar results have been reported by Scagliono et al. (21) . This is in line with an earlier study suggesting a protective effect of breast-feeding against obesity at 12 to 18 y of age (51) . The gross efficiency of dietary nitrogen utilization for lean body mass deposition was almost 50% lower in formula-fed than in breast-fed infants, despite significantly higher nitrogen and energy intakes of the formula-fed group (52) . In addition to protein, other nutrients, or even nonnutrient factors, cannot be excluded as possible effectors of body fat mass in breast-fed versus formula-fed infants. In any event, although mechanisms are still obscure, it would be worthwhile to explore the possible effects of dietary protein intake on the development of later obesity.

In this context it is interesting to note that formulas for low birth weight infants (protein 16–20 g/L; 5.3–7.7 g protein/MJ) contain approximately twice the protein content of breast milk. In various studies, associations between protein intake and growth velocity and weight gain have been reported (47 ,49 ,53) . It might be suggested that people who are small in early life and then grow rapidly are more at risk for metabolic syndrome or obesity than those who remain small. Results from the Avon longitudinal study of pregnancy and childhood (ALSPAC) indicate that children who showed catch-up growth between birth and 2 y of age had lower weight, length and ponderal index at birth but were heavier, taller and fatter at 5 y of age compared with other children (54) . In a Finnish study, the highest death rates from coronary heart disease occurred in boys who were thin at birth but who also showed increased catch-up growth until age 11 y, so that they had an above average body mass (55) . It is likely that those who where thin at birth received compensatory feeding, i.e., additional energy and/or protein, to support catch-up growth or to increase growth velocity. Thus, it is important to consider whether growth velocity may be a relevant influence in the causal pathway of obesity as suggested recently for fetal programming of metabolic disease (7) .

The biological mechanisms responsible for a potential relationship between early life dietary protein intake and obesity may be linked to glucose metabolism. It has been shown in formula-fed infants and adults that high protein intakes are associated with a higher insulin secretion and a higher hepatic glucose output (49 ,56 57 58) . By contrast, in experimental animals, protein restriction during fetal life is followed by an impairment of ß-cell mass development predisposing them to glucose intolerance in later life (59 ,60) . Insulin-like growth factor (IGF)² binding proteins and circulating IGF-I levels are regulated by dietary protein intake (61 62 63) . Dietary protein increased IGF-I expression in pig adipose tissue (64) . Insulin and IGF-I are required for differentiation of preadipocytes and inducing adipogenesis (65) . In contrast, low amino acid concentrations induce IGF binding protein-1 expression and participate in the down-regulation of growth (66) . In this context, it is relevant that decreased versus adequate as well as increased versus adequate dietary protein intakes lead to characteristic decreases of certain circulating dispensable and indispensable amino acid concentrations (63 ,67 ,68) . In regard to effects of dietary protein on fetal growth, it is interesting to note that certain placental amino acid transporters are down-regulated by maternal protein deprivation (69) .

In summary, despite numerous reports of studies in animals, there is still no conclusive evidence from human studies that low protein intake during gestation leads to low birth weight and subsequent metabolic disturbances in early childhood or adulthood. Currently there is also only weak epidemiological evidence supporting a link between high protein intake during early childhood and the development of obesity in adults. Unfortunately, it is often difficult to interpret much of the epidemiological evidence in humans due to the inability to control many influential factors, most importantly, the accuracy of reporting of dietary intakes and habits. Eating habits can change dramatically throughout pregnancy and this makes it necessary to record nutrient intake and anthropometric parameters at more than two time points during pregnancy, and, if possible, before conception. One proven method of validating protein intake is the use of 24-h urine collections and the control of confounding factors must be appropriately considered. Especially, subgroups who fail to meet or largely exceed current dietary protein recommendations should be identified. In addition, intervention studies in animals can support or question epidemiological results. Particularly, the question whether dietary protein intake pre- and postweaning affects body fatness needs to be addressed in well-designed and controlled animal studies. Also, possible interactions between birth weight, growth velocity and fetal and postnatal protein nutrition deserve attention. Should a link between dietary protein and adiposity be experimentally confirmed, the next step would be to uncover the underlying mechanisms, such as protein-related alterations of energy expenditure, influences on hormones and growth factors and adipose tissue metabolism in response to perturbations of amino acid homeostasis brought about by amino acid regulation of gene expression.

	ACKNOWLEDGMENTS

 
I thank Heiner Boeing, German Institute of Human Nutrition, for constructive discussion of epidemiology. Brian J. Bequette, Rowett Research Institute, is acknowledged for English editing of the manuscript.

	FOOTNOTES

 
² Abbreviation used: IGF, insulin-like growth factor.

Manuscript received December 1, 2000. Initial review completed April 16, 2001. Revision accepted April 16, 2001.

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