Early Protein Intake, Metabolic Programming and Later Obesity

Editor(s): Atul Singhal.

Early Protein Intake, Metabolic Programming and Later Obesity

Atul Singhal

The idea that nutrition in early life may influence, or programme, later health first emerged in the 1960‘s with the work of McCance (Singhal A, Lucas A., Lancet 2004). He showed that rats raised in small litters, and therefore overfed post-natally, were larger in adulthood.

In humans, the strongest evidence for nutritional programming has emerged for the benefits of breast-feeding. Breast-feeding compared to formula feeding has been shown to reduce the propensity for obesity, dyslipidaemia, high blood pressure, and insulin resistance, the main risk factors for cardiovascular disease. Although the mechanisms for these effects are not known, we proposed that faster growth (upward centile crossing) as a result of relative over-nutrition in formula fed compared to breast-fed infants could adversely affect later cardiovascular health – the Growth Acceleration Hypothesis (Singhal A, Lucas A., Lancet 2004).

Consistent with the growth acceleration concept, many studies in healthy infants have confirmed an association between faster weight gain in infancy (upward centile crossing for weight) and later obesity, insulin resistance, and higher blood pressure.  This association has been seen in >30 studies (summarized in 5 systematic reviews – (Singhal A.,Proc Nutr Soc. 2016 / Patro-Gołąb B et al., Obes Rev 2016) including an individual-level meta-analysis in 47,661 participants from 10 cohorts (Druet C, Stettler N, Sharp S et al., Paediatr Perinat Epidemiol 2012). These effects are seen in both high- and low-income countries, for both weight gain and linear growth, in in- fants born preterm or at term, in infants with normal or low birth weight for gestation, and in both breast-fed and formula-fed infants (Sa- vage JS, et al., JAMA Pediatr. 2016). In fact, the adverse long-term effect of faster early growth appears to be a fundamental biological phenomenon seen across animal species as diverse as insects, fish and mammals1. The magnitude of the effect is substantial. For example, over 20% of later obesity risk can be attributed to a high rate of infant weight gain; the relative
risk of obesity associated with faster weight gain in infancy ranges from 1.2 to as high as 5.7; and a 3 mm Hg reduction in population diastolic blood pressure associated with slower infant growth would be expected to prevent >100,000 cardiovascular events/year in the USA alone (Singhal A, Lucas A., Lancet 2004 / Patro-Gołąb B et al., Obes Rev 2016).

Central to the growth acceleration hypothesis is that fact that breast-fed infants grow more slowly than those fed formula probably because of the lower protein content of breast-milk compared to cow’s milk based formulas. (Fig 1) Formula-fed infants receive
on average 0.5g/kg/d greater protein than breast-fed infants which could increase later adiposity possibly by mechanisms that involve programming of hormonal factors that affect appetite regulation and adipose tissue deposition6. This difference in protein intake is most marked between 3 and 12 months of age when the protein concentration of breast-milk falls rapidly (Michaelson KF, Greer FR., Am J Clin Nutr 2014). Therefore, a lower protein intake in infancy that leads to slower weight gain might improve long-term health and particularly the risk of obesity – a hypothesis now confirmed in 5 randomised controlled trials (as reviewed – (Singhal A., Proc Nutr Soc. 2016).

In the first RCT, infants born preterm and randomly assigned to a protein-enriched diet, that promoted faster weight gain in the first few weeks after birth, had higher blood
pressure, fasting concentrations of insulin, cholesterol, and C-reactive protein, and greater risk of obesity in adolescence than controls. Similarly, infants born small for gestation at term and randomly assigned to nutrient-enriched formula that increased weight gain had higher diastolic blood pressure at age 6–8 years and, in 2 trials, 18–38% greater fat mass at age 5–8 years than controls (Singhal A., Proc Nutr Soc. 2016). (Fig 2)

In the largest study, the European Childhood Obesity Trial, infants randomised to a higher protein formula (2.05 g/100ml in first 6 months
followed by 3.2 g/100 ml to 12 months of age) had 2.4x greater risk of obesity at age 6 years than those receiving standard infant formula
(1.25 g/100 to age six months followed by 1.6 g/100 ml to 12 months) (Weber M, Grote V, Closa-Monasterolo R et al., Am J Clin Nutr 2014).

Finally, in Chile, infants of mothers with a BMI >25 kg/m2, who were randomised to new low-protein formula between 3 and 12 months of age (protein: 1.04 g/100 ml, energy 62.8 kcal/100ml) had lower risk of obesity at age 2 years than those assigned to a standard prote- in formula (protein: 1.77g/100 ml, energy: 65.6 kcal/100 ml) (Inostroza J, Haschke F, Steen- hout P et al., JPGN 2014).

Public Health Implications
The strength of the evidence supporting the growth acceleration hypothesis is challenging established public health practices. Professional bodies such as the Institute of Medicine in the US and the Royal College of Paediatrics
and Child Health, and the Scientific Advisory Committee on Nutrition in the UK have recognized the role of faster infant weight gain in increasing the risk of long-term obesity. The WHO growth charts based on slower growing exclusively breast-fed infants are now widely used and can help in the prevention of over- feeding in infancy. Furthermore, contrary to previous medical and public opinion, promoting catch-up growth by nutritional supplementation in healthy term infants born small for gestation may not be appropriate (Clayton PE, Cianfarani S, Czernichow P et al., J Clin Endocrinol Metab 2007). Finally, the benefits of a slower rate of infant weight gain
as seen in breast-fed compared to formula fed infants has led to changes to infant formula to try to reduce the risk of over-feeding in formula-fed infants. These include reduction in the protein content of infant formulas and changes in recommendations for the composition of formula.

For example, the European Food Safety Authority recently recommended a reduction in the maximum permitted protein content in in- fant formula and suggested that ‘infant formula and infant follow-on formula should ensure that the growth and development of infants fed infant formula are similar to those of infants who are exclusively breast-fed during the first 6 months of life’ (EFSA NDA Panel, EFSA Journal 2014). Therefore, using infant formulas with lower protein content could slow down the rate of weight gain in formula fed infants (closer to those given human milk) and have long-term benefits for health, and particularly for the risk of obesity. Finally, cow’s milk, a major source of excess protein for young children in richer countries, is not recommended
below 12 months of age and even restricted to <500 ml/d in toddlers.

Clearly, the risk-benefit of faster early growth depends on the population involved. Faster weight gain may improve long-term cognitive function in infants born preterm and has short- term advantages for morbidity in infants with low birth weight from low-income countries (Singhal A., Proc Nutr Soc. 2016). However, in healthy infants born at term, the key message for health care professionals and parents is that ‘bigger is not necessarily better’.