Fat, Fate, and Disease : Why we are losing the war against obesity and chronic disease (27 page)

The first reason is that it has been hard for many of us to see what can be done about the problem from the life-course perspective. Human development is seen as being too complicated. It is hidden from view, at least in the womb, and seen as being protected from external influences, good or bad. Development has been seen as encapsulated, separated from the world outside. But, as we have shown, this idea is completely wrong. The research over the past 25 years reveals without a doubt that the fetus can, and does, respond to external influences, and that its responses alter the course of development itself to set the risk of a range of later problems such as obesity.
We have seen how virtually every baby’s metabolic fate is tied up in its experiences as a fetus: whether the mother is fat or thin, whether she has diabetes, whether she is dieting, whether she is young or old, whether it is her first baby, etc. And we have seen how new data suggest that this leads to changes in the epigenetic state of the offspring. And we have seen that some new and provocative data suggest that the father’s lifestyle and physical state can also affect the offspring—it may well be that obese fathers have epigenetic changes in their sperm which pass on a greater risk of obesity and diabetes to their children. And there is growing evidence that interventions and actions in infancy and childhood can also have long-term benefits.

Given the mass of data, there is no longer any excuse for ignoring the importance of the beginning of life to our later health. Indeed the data we have reviewed about epigenetic gene switches at birth predicting whether a child is more or less likely to get obese are so compelling that it must shift the focus of prevention from the adult to the parent, fetus, and infant. The clinical, epidemiological, and experimental data all agree; the practical implications of the research discoveries showing that we start to face the modern world well before and soon after we are born can no longer be overlooked.

Prevention is always better than treatment. We now know that prevention must start before we are born and probably before we are conceived. The paradigm is very simple. While the molecular changes that start in our bodies before birth may be subtle, they change the way we will respond to the nutritionally rich world we will progressively face after we are weaned. Thus some people are set up early in life to be more or less likely to put on weight, to develop insulin resistance, or to have faulty blood vessels. Because they are more sensitive to the challenges of the modern world, the effects become greater and greater over time. It may only be a few hundred grams a year at first but over time frank obesity and its complications will develop. That is the insidious nature of this process and that is why it
is generally too hard to intervene once the processes are clinically apparent. Our efforts must shift to the very beginning of life.

When we embarked on this research, we had suspected that this early phase of life was important and that it would involve most babies, not just the growth-retarded ones that the early researchers in this field had focused on. But frankly, we have been surprised by how important this effect seems to be—the studies on gene switches measured in the umbilical cords of babies from Southampton have shown the prenatal factors operating before birth to be much more important than we had imagined.

The neonatal and infant periods are also very important—breastfeeding for several months can make a difference to the later risk of obesity and disease. Both poor nutrition in infancy and excess nutrition, from the inappropriate use of infant formula and other foods, can have long-term effects. Paediatricians and nutritional scientists in London have shown that bottle-feeding can adversely affect intelligence later in life. Extreme under-nutrition in infancy impairs brain development. If it is followed later by better nutrition, this mismatch can set the child up to subsequently become obese and put him or her at risk of disease.

Unfortunately nutritional science has not received enough attention or support in the past few decades, while the search for the genetic basis of disease has taken prominence. So our knowledge of what constitutes optimal nutrition for the mother during pregnancy and lactation and for the infant after weaning is remarkably weak. Yet most research authorities believe that this work has already been done. They are wrong. They are caught in a mindset that nutritional research is old-fashioned and simply focuses on deficiencies and excesses. The new science of epigenetics changes this dramatically.

The recognition that epigenetic markers can be used to identify the effect of nutrition during pregnancy and probably also during infancy now gives us a way of moving forward. We can envisage trials, and are now planning them, where we can learn from the
epigenetic state of babies what the best diet for the mother or the baby should be. We would imagine that over time this will be an enormously fruitful area. We may be able to develop foods for mothers while they are pregnant or lactating, and for babies after they are weaned, which are designed to produce the optimal epigenetic state and the lowest later risk of disease. This is not fanciful—while it may take a decade, early efforts in this direction have started.

As so often in biology, thinking about other species can give us insights into our own biology, or at least make us pause for thought and consider other ways of looking at our own bodies. Take marsupials for example. These intriguing animals diverged from our early mammalian ancestors about 150 million years ago. Unlike most mammals, they have a very primitive placenta and give birth to a very immature embryo which has to be nursed in the mother’s pouch for many months before it can leave for even a few minutes. The wallaby’s baby joey has at birth a simple sense of taste which allows it to crawl up onto a teat in the pouch—it is literally only 1 or 2 cm long at this stage and is extremely fragile. It does not even have fully formed lungs as yet, but can absorb oxygen through its immature skin which has no fur. It grows over the next few months fed entirely on its mother’s milk. But this milk is quite remarkable, because it changes in its composition dramatically at different stages during the joey’s development—one protein disappears, another appears, and there is a biochemical dialogue between mother and joey to provide the food it needs to optimize its development at a particular time.

Marsupials are very different from other forms of mammals because lactation has to do what the placenta does in most mammals—provide nutrients to embryo and fetus until it can start on its path to independent life. Because the joey’s development in the pouch takes so long, while still suckling one joey the mother may give birth to another, much younger embryo, which also crawls up to reach a teat. Now there are two joeys in the pouch, of very different ages and maturity, and with very different requirements in terms
of milk composition. Their demands are met by the mother producing a different type of milk from each of her teats—an apparently unique process in which these mammary glands respond to signals from the joey about its age.

These processes do not operate in humans, and in any case women cannot usually become pregnant while still lactating. This is an evolved mechanism which allows us to space our children out, as we know that infant mortality rises if human babies are born too close together. Marsupials have a very different strategy, based on having more offspring. But notwithstanding these differences, it is likely that there are many more subtleties to human milk than we understand. Human milk’s composition does change over time. Colostrum, the thick product of the mammary gland soon after birth, is rich in proteins, hormones, and antibodies and has a critical role in establishing early immunity against infection. It is nothing like the milk that is produced once lactation is established and that too changes its composition as lactation progresses. Human milk contains hundreds of different molecules and not all women have the same mix. Could these different compositions play a role in influencing infant development? There might be a reason for this—perhaps an evolutionary one—but it is not yet known.

We know that whether a baby is fed on breast milk or formula from soon after birth changes the mix of bacteria that colonize the gut and we are beginning to realize how important that might be to future health. It is certainly another reason to promote breastfeeding. The mix of bacteria which is established in our gut in infancy essentially remains with us for life. One of the most exciting areas of medical research is using the power of modern molecular biology to sort out the thousands of strains of bacteria that inhabit our gut. Generally these bugs inside our bodies are very useful. They help by predigesting our food and play a major role in determining our nutrition and our metabolic health. We know that people with diabetes have different patterns of gut bacteria. We also know that how we
develop this internal family of gut bacteria influences whether we get allergies—that is why many baby formulas and yoghurts for older people contain probiotics—strains of benign bacteria thought to be helpful and to promote health. In addition some milk products contain prebiotics—chemicals which are thought to enhance the growth of healthy bacteria.

Might it be that the mother’s characteristics influence the composition of her breast milk more than we realize? A worrying trend is that as women become more obese the composition of their milk does indeed change. And over the past 20 years the ratio of omega-6 to omega-3 fatty acids in human breast milk has doubled, because many modern foods such as margarine and corn-fed meats contain high levels of the generally unhealthy omega-6 fats. From what we know about good and bad fats this is a worrying and unhealthy trend. The frightening implication is that human breast milk may well not be as healthy as it was a generation ago—even though it still provides clear advantages to the infant in terms of immune support and breastfeeding assists emotional bonding with the mother. Furthermore, because breastfeeding is driven by the baby, rather than by the mother’s choice, or by practical matters such as the size of the teat on a feeding bottle, the risk of overfeeding is much lower. Generally, breastfed babies receive fewer calories than bottle-fed babies.

What happens during development may also play a major role in establishing food preferences and appetite later in life. We have seen how rats and humans who have been under-nourished early in life are more likely to require more calories to feel satiated later in life and that they prefer different foods, such as high-fat ones. These changes in appetite control appear to be associated with alterations to the wiring of the hypothalamus, the part of the brain which controls appetite.

Food preferences are informed by taste and smell. There are a limited number of distinct tastes we can detect, but we can distinguish between a wide range of flavours because we have a very large
number of different cells in the brain system connected to our nose and palate. Between them, these smell and taste receptors give us the capacity to, on the one hand, savour a fine Bordeaux and make all sorts of comments on the intricacies of its bouquet and taste, yet reject rotten or unripe food on the other.

Human babies are born with a very limited number of tastes, in fact just two—sweet and salty. However, their palates can be broadened by the range of foods they are subsequently fed, and there is good evidence that what a baby is weaned onto, and how it is weaned, affect its later appetite control and food preferences. For example, repeated exposure to vegetables, even if they are initially disliked, can lead to greater acceptance of these foods over time.

There is also evidence that what a mother eats during pregnancy can lead to changes in her infant’s food preference. For example, infants of mothers who drank carrot juice during pregnancy preferred carrot-flavoured cereals compared to those whose mothers did not consume any forms of carrot. Indeed, animal studies have shown that the mother’s diet can change the balance of specific receptors in the brain which process odours. Furthermore, because flavours from food consumed by the mother can be directly reflected in her milk, maternal diet during lactation may also have an effect. Experiments have shown that exposure to flavours such as garlic through breastfeeding can determine the infant’s eventual liking and acceptance of that flavour. So developmental exposures can influence eating behaviour in many ways.

We now know that in the first few years after birth, the brain circuits controlling energy regulation are established. These certainly include those related to appetite control and possibly also to exercise patterns. Whether these are hard-wired or are simply entrained behaviours that result from what the child has experienced is not entirely clear, but either way patterns for life are established very early.

There can be no doubt that the micro-world of the family that a baby is born into influences the way it grows up. If it is born into a
family where excess eating is the norm, body image and behaviour will be affected. Food surveys have been done in many countries to see what babies are fed on. What these show is somewhat alarming. For example, French fries have become the most common vegetable given to infants in the United States. These studies consistently show that infants are being fed unhealthy, inappropriate diets with excess calories especially from fats and high-glycaemic-index sugars.

First-born babies may have a different biology owing to differences in the level of maternal constraint of their growth before they were born, but they are also treated differently. In Asia the sole child, especially a boy, is often called the ‘little emperor’, and his every whim is indulged by parents and grandparents.

Many attitudes passed down through generations date back to a time when illnesses such as gastroenteritis were common, and these limited the child’s growth. So grandparents often have the attitude that a fat baby is a healthy baby—this is a belief that is no longer wise because the fat baby, at least in a Western country, is generally a baby at risk. In the West, how often does a person from the older generation express concern when a baby does not look chubby? The response of naive and concerned parents is almost inevitable and is often reflected in overfeeding and childhood obesity. Habits and perhaps their biological consequences are set up for life.