Fat, Fate, and Disease : Why we are losing the war against obesity and chronic disease (22 page)

More recent observations in relation to humans have studied what happens in surrogate motherhood. Where an embryo is donated by one woman to another, and thus develops in the uterus of the second woman, the fetus born is closer in size to other children of the recipient mother than to those of the donor mother. So it seems clear that the mother’s intrauterine environment is more important, in this case, than the genetic make-up of the fetus.

The degree of constraint can vary, and is greater in the first pregnancy in a woman’s life. This makes sense in evolutionary terms because a woman’s pelvis does not reach maximal width until four years after her first period. In the past it was inevitable that she would have been pregnant well before then—fertility is usually good two years after the first period. The underlying mechanism may involve the blood vessels supplying the uterus, which normally dilate and increase their flow during pregnancy, but are not as conditioned to do so in the first pregnancy as in subsequent pregnancies. Another reason might be the sheer demands on resources which pregnancy makes. If the woman is a teenager and her body is still growing at the time that she becomes pregnant, the question arises of whether it would be better to devote those resources to her growth or to the growth of her baby. From an evolutionary point of view the answer is unequivocal—it is better for the resources to be used to grow the mother than her offspring. After all, even if the pregnancy fails she
can become pregnant again, and this accords with the harsh but realistic evolutionary process.

So, on average, first-born children are about 100 g smaller than subsequent children. This may not sound like much, but remember that we are not focused on birth weight, but on the signals which the intrauterine environment might give the fetus so that it can predict its future nutritional environment, and birth weight is only a poor indicator of these signals.

Shorter mothers tend to have a smaller pelvis, so again maternal constraint is greater. In places like India where there are multiple generations of stunting due to inadequate childhood nutrition and infection, birth weights are much lower than we have come to expect in the West. The average birth weight in some parts of India might only be 2,600 g—a weight we would regard as being growth-retarded in the West. Indeed the World Health Organization regards a birth weight of less that 2,500 g as being growth-retarded, but this would encompass 40 per cent of some Indian populations, many of whom may be nonetheless healthy at birth.

Women who have their first pregnancy after the age of 35 also tend to give birth to smaller babies. This is an increasing problem as more women choose to do so for economic or social reasons. And many of them need in vitro fertilization for, sadly, fertility is declining by that age. IVF is associated with a higher incidence of twins and this leads to greater maternal constraint. This is because there is a limit to how much nutrition the mother can deliver to her fetuses, so fetal development will be even more constrained with triplets or quadruplets.

Considering smaller family size, short mothers, elderly first-time mothers, and multiple pregnancies, not to mention maternal and placental disease, we can see that for many populations well over 70 per cent of fetuses are likely to have a constrained perception of the nutritional world ahead of them.

There are biological reasons why it is safer to predict living in a bad nutritional world after birth than a good one. First, as we saw in the Jamaican infants, being set up to predict a bad nutritional world may make us more likely to survive famine. For many years this was thought to be the main reason behind these processes, but it now looks less certain that our Palaeolithic ancestors had to deal with much famine. We now think that the processes are more subtle. Predicting a harsh world gave the offspring a tendency to lay down fat when they could. This is important as the large and growing human brain has a high demand for energy. It does not reach full size until about seven years of age, and by that time the Palaeolithic child would no doubt have been exposed to multiple episodes of diarrhoea and other infections. To be primed to lay down fat as an energy store would thus be helpful. Furthermore, mild to moderate adiposity promotes fertility. The problems that come from being set on a path of predicting a poor nutritional environment appear only later in life, and then only if we live in a nutritionally rich environment.

And that is the key point—prediction is fine if there is an approximate match between what is predicted and what happens. We say approximate because every one of us has flexibility in our metabolic capacities and copes quite well with a range of energy loads. But, as the rat experiments showed, the greater the degree of mismatch the more likely we are to suffer the consequences in terms of obesity and disease. The greater the degree of maternal constraint the greater the likelihood of mismatch, and the greater the richness of the world out there the greater the degree of mismatch. Indeed, it turns out that all those groups we discussed—first-born children, children born prematurely or growth-retarded, children who are twins, children whose mothers eat less than optimally—are generally all at greater risk of obesity, diabetes, and cardiovascular disease.

There are also some examples of mismatch driven by human behaviour. Smoking reduces the passage of essential nutrients such as amino acids across the placenta to the fetus, and some
environmental toxins can do the same. Excessive exercise in pregnancy can affect fetal nutrition too. There is some evidence that bottle-feeding increases mismatch and hence the risk of obesity later in life, because infant formula provides much more energy than breast milk. However, unbalanced modern diets can also affect breast milk quality, and this is an area about which we do not have much information and where more research is urgently needed.

Because diabetes and cardiovascular disease have insidious onsets, the greater the mismatch the earlier in life the clinical disease is manifested. We can see now how the graded relationship between birth size and disease risk is established. While maternal constraint does not lead to abnormal fetal growth retardation, it may subtly affect growth within the normal birth weight range, and thus affect later risk.

There is another way in which mismatch occurs.

Humans move—they migrate and change their habitats. We have done this as a species from the time that our ancestors migrated out of Africa about 70,000 years ago, but the modern world has seen more migration than ever before. Some was forced—particularly by the slave trade and by the consequences of colonization and warfare. Much was voluntary, although economic or political in origin: the many thousands of Italians who travelled to the USA at the end of the 19th century and the beginning of the 20th century to seek a better life, the immigrants from Puerto Rico and many other Hispanic countries who moved to North America, the evacuation of the Falasha Jews from Ethiopia to Israel, and more recently the movements of people from eastern to western Europe and from North Africa to Italy. Nearly always these people are moving from a poor environment where they may be persecuted, under-nourished, or exploited,
to a land in which they hope there will be more security and better education and healthcare. And everywhere people move from the countryside to the city. For the first time in our history more people now live in cities than in rural areas. They too come hoping for employment, for their children to get a better education, and to be better connected to modern society.

We say ‘hoping’ because very often their dreams are not fulfilled. All too often people migrating from low-income parts of the world to supposedly higher-income parts end up as the urban poor in their new homes—from the frying pan into the fire. This is clearly the situation in many parts of India where every month thousands of rural poor move to the cities in search of a better life.

Think of two brothers from rural Maharashtra who move to Mumbai and manage to raise a loan to buy an auto-rickshaw. They hope they will soon be sufficiently well-off financially to bring their families from the country too. It does not work out. After many months they decide that their wives should move to Mumbai, to assist with the cooking and washing and possibly to take on some outworking at home. They become ensconced in one of the slum areas of Mumbai. In time, several children are born. Another family has been established in a cycle of disadvantage and poverty. In the process, their lifestyles and those of their children have changed dramatically. The hard physical labour of working on a subsistence farm in the countryside is now replaced by sitting in a rickshaw in heavily polluted traffic or at home over a sewing machine in bad light. The city diet is rich in fat and sugar and salt as fast food outlets are the easiest way to eat during a busy working day—although it’s pan puri here rather than McDonald’s. Even the kind of fat consumed has changed. In the country, the diet would be low in fat apart from wedding and feast day food cooked in ghee, made from clarified butter. In the city, the oil in which much of the food is fried is a metabolically dangerous hydrogenated fat of questionable industrial origin.

The educational system or healthcare system in many slums on the edge of cities is no better than it was in the country. We can easily see how the biology of the woman born in rural India, of short stature, thin, and with a relatively small womb and pelvis, can give birth to a child who is totally mismatched to the life of urban Mumbai or Kolkata. These processes can explain the rapid increase in obesity among children which has occurred over a generation in migrants and where there have been rapid changes in diet and lifestyle through the developing world. The effects are just as dramatic—or more so—as those resulting from increased affluence in parts of the developed world.

A terrible tragedy is unfolding in parts of the South Asian subcontinent—as it is across China, Africa, and South America. Increasingly the mismatch which accompanies the rapid shift to a Western lifestyle, usually within a generation, is producing a wave of young people with obesity, and changes in their biology have put them on the path to diabetes or heart disease, if indeed they do not already suffer from them. These people may have to take drugs for the treatment of these conditions for the rest of their lives—if they can afford it—and slowly but surely the diabetes and circulatory problems will take a toll on many organs in their bodies. It will reduce kidney function, which means that an increasing number of them will go into renal failure and may need dialysis or kidney transplants. These are expensive and there is a limited source of donors, so many of them will die. The problem has also fuelled an illegal trade in organs—from donors (or their families acting for them!) who have ‘donated’ a kidney for cash.

The problems do not stop at the kidney. Diabetes will affect the blood vessels in many of the muscles in the body, making it hard for the person to exercise and even to look after themselves. The poor blood supply, especially to their lower limbs, will lead to ulcers, infections, and a high risk of needing an amputation. The diabetes will affect the little blood vessels supplying the retina of the eye, leading to blindness. This situation is getting worse by the year and it is
calculated that by 2030 the number of diabetics in India will reach nearly 80 million.

The health costs of the condition will be enormous. All this in a country that cannot afford to vaccinate all its children against life-threatening diseases such as polio, measles, and whooping cough—single-shot vaccinations which cost a few dollars and give lifelong protection. How can such societies afford high-cost medical therapies for such a large part of the population?

And the challenge is no different in China, Indonesia, Mexico, Brazil, or the Gulf states …

We may have answered the question of why a poor start to life can lead to a greater risk of developing diabetes and cardiovascular disease, but to be able to stop the problem we have to have a clear idea of the biological processes that lead to this.

The first clues to answering this question come from India itself. Consider the babies born there: they are small babies but not necessarily thin babies. Even if they look thin they may have more fat on board than might otherwise be expected. Chittaranjan Yajnik is a renowned diabetes specialist in Pune, a city about 100 miles inland from Mumbai. Some years ago he started to make some simple measurements of the sizes and shapes of Indian babies at birth, analysing (with new scanning techniques as they became available) the composition of their bodies and comparing them to that of babies born of white parents in the UK. As we have already described, Indian babies tend to be smaller than European white babies, weighing almost 600 g less on average at birth. The surprising finding was that these babies were not equally small in every aspect of their bodies. They had relatively less skeletal muscle in their bodies and relatively more fat than their European
counterparts. This fat was not under the skin but largely inside their abdomens, the visceral fat we described earlier as being most associated with later disease. Yajnik called this the ‘thin outside-fat inside’ baby.

Putting our evolutionary ideas into the story, we can see that this is a sensible body composition for these babies. If we predict a nutritionally limited future, we invest less in growth of metabolically active tissue like muscle and lay down more fat in order to have an energy reserve for when it is needed.

If the situation of the thin-fat Indian baby indeed represents normal biology—and we think it does as part of a response of the fetus to the conditions of prenatal life—then we might expect to find such variations even in Western babies. They may not be so obvious, but they should be there.

This is precisely what has been found in Southampton Women’s Survey babies. Guttorm Haugen and Torvid Kiserud are obstetricians from Norway who worked with the Southampton investigators using advanced ultrasound techniques to study the way that blood flows around the fetal body in late gestation. In women who were relatively thin and who consumed an unbalanced diet—high in red meat, sugar, crisps, cakes, and white bread, but low in fruit and vegetables—the patterns of blood flow were different from those in fetuses whose mothers consumed a healthy, balanced diet. The amount of blood coming back from the placenta and going to the fetal liver was increased, and the amount going to the developing fetal heart and brain was correspondingly reduced. And this pattern of blood flow was associated with greater fat in the babies at birth—they seemed to be like the thin-fat Indian babies. Subsequent studies have shown that this difference is still present in the same children at the age of four, so it appears that the trajectory of fat deposition which starts before birth continues throughout infancy and early childhood.