Fat, Fate, and Disease : Why we are losing the war against obesity and chronic disease (24 page)

We are most definitely not, for two reasons …

Firstly, much of the variation in fetal experience that causes epigenetic change is likely to be subtle. Mothers can do nothing, for example, about their height, or whether this is their first pregnancy, so any idea of blame is completely inappropriate. However, with the new knowledge we are gaining we can develop much better advice for mothers about how they should care for themselves and their developing fetus during pregnancy. Current advice is not good and better advice is badly needed. We will return to this point.

Secondly, fathers do really matter too. While the results are only just starting to emerge, there is enough experimental data coming from studies in rats and mice to show that fathers can transmit signals through their sperm which also affect their baby’s epigenetic state. Certainly, fat or stressed male rats can father offspring who become insulin-resistant or obese. And from studies using chemical toxins we know that epigenetic changes can be transmitted from one generation to the next through sperm.

We are just beginning to scratch the surface of the science here, but it is safe to say that what either parent does might affect their
offspring. We know more about the maternal effects and it is inevitable that the mother has a greater influence—through the months of pregnancy and nursing, if not for any other reason. But if we are to help the next generation to be healthier by improving their developmental environment, we must enlist the help of both parents, and not blame either of them for processes which are all part of the nature of being human.

Mothers are changing—many are getting fatter and more and more women suffer from a transient form of diabetes during pregnancy. Can these changes also contribute to the risk of diabetes and heart disease in the next generation? There is compelling evidence that they do.

Maternal obesity is now a major concern and the focus of much recent investigation. This has shown that women who are obese are more likely to give birth to babies who themselves will become obese as children. All the signs suggest that these children will go on to have a higher risk of diabetes and cardiovascular disease.

The big question is—why? Why doesn’t each generation start afresh, only becoming obese if its members consume excess energy or do not exercise enough? After all, this is the implication of the widely championed argument that these are the most important risk factors for obesity. Its advocates would argue that it is simply that people born into families where other members are obese learn the
same habits of gluttony and sloth as their parents. Clearly children do learn from their parents and pick up exercise and feeding habits very early in life. In fact, that is a major argument for giving greater emphasis to early life as a point for intervention.

But there is more to it than this—in animal experiments conducted in many research centres it has been shown that giving high-fat diets to pregnant animals leads to the mothers giving birth to pups which themselves become fat. For example, when Maqsood Elahi and Felino Cagampang in Southampton fed female mice a high-fat diet from the time of puberty, they gained weight, and interestingly their offspring ate more, exercised less, had high blood pressure, became fat, and showed inflammatory markers in their blood—they looked very much like humans with the metabolic syndrome. The effects were worse if the offspring were also given the same high-fat diet as their mothers. As Kim Bruce and Christopher Byrne showed, these offspring laid down more fat in tissues such as the liver, so it seemed as if they had been primed to make the most of a high-fat diet, although if given it continuously they became sick. The parallels with the human condition are striking. Deborah Sloboda and Mark Vickers made similar observations in rats in Auckland and found almost identical results. For example, they fed female rats high doses of fructose, the sugar found in soft drinks, and showed that the offspring had unhealthy livers.

These effects, produced by feeding a high-fat diet to a pregnant rat or mouse, cannot be due to learnt behaviour or to genetic factors. The ‘obesity begets obesity’ phenomenon is yet another demonstration of the impact of development, of very early life experiences, in establishing our metabolic control and risk of disease.

But that still does not answer the
why
question: why is it that we have evolved with a biology such that when our mothers eat a high-fat diet we have a great risk of becoming fat and getting diabetes? And as we saw in the last chapter, we might also have some additional risk when our fathers are obese.

The first point to make is that parental obesity and exposure to very high-fat diets is not likely to be something our forebears experienced very often. Through most of our evolutionary history we were probably relatively lean and rarely had much access to high-fat foods. Some individuals may have become obese but they would have been rare. Accordingly we never evolved to cope with exposure to such high-fat foods and neither our maternal nor our fetal physiology is designed to deal properly with them. But how does this explain how obesity is passed on to the next generation?

We saw in the last chapter that a pregnant woman’s consumption of an unbalanced diet—particularly one that signalled a poor nutritional world—was likely to lead to her fetus laying down more fat in its body. We believe that this evolved because it would have provided some survival advantage for the infant under predicted difficult and unreliable conditions after birth. In particular, having extra fat as a child provides a fuel reserve to feed the hungry and rapidly growing brain in infancy and childhood, especially after weaning when the risks of under-nutrition might be high—from infection, famine, conflict, etc.

Starting life poorly can lead to relative obesity later in life and many women who are obese do actually consume an unbalanced diet. Indeed, somewhat paradoxically, many infants born to obese women are slightly growth-retarded, reflecting this unbalanced nutrition or other problems of pregnancy. They have started on the pathway to obesity that we described in the last chapter. But how does this explain why the babies born to obese mothers, of normal or large size, go on to become obese?

There are at least two ways of explaining the processes which are going on. As so often in science, they are probably both correct, but we do not know the circumstances under which each operates; they may even operate simultaneously.

The first, and most commonly held, idea is that the consumption of a high-fat diet by the mother literally produces toxic effects on her and on the placenta and so affects her growing fetus. These toxic effects build up as she becomes obese. The toxic processes in question involve free radicals, unstable molecules which use oxygen chemically to oxidize many components of the body, changing their function.

Exposure to a degree of such oxidative stress is a fact of life, because we make some free radicals all the time—it is a consequence of living in an atmosphere that contains 21 per cent oxygen. We cannot survive without it, even though, paradoxically, it is slowly killing us. Many of the processes of ageing are associated with the slow and inevitable damage from oxidative attack. However, the body uses a range of antioxidants, some enzymes, and vitamins C and E to destroy free radicals and limit this damage. But these systems can be easily overloaded. So it may be that excess fat leads to more free radicals which damage the placenta and its blood vessels, limiting nutrient supply to the fetus. The free radicals may even cross the placenta, attacking the fetal tissues directly. So this theory can certainly explain some of the evidence of damage seen in the placenta of obese humans and animals, and it can explain why some obese women give birth to babies that are smaller than average because of poor placental function. And so a pathway to developing obesity later is established.

We will discuss the second theory in more detail later in this chapter in relation to the diabetes of pregnancy. When excess energy gets to the fetus it can stimulate the fetus to make more insulin. Fetal insulin causes the developing fat cells to increase in number—so these babies are born with more fat cells. And if we start life with more fat cells, in the modern world they can become readily loaded with fat, and because we therefore have more capacity to store fat it becomes much easier to become obese.

An extension of this argument runs as follows. Some degree of body fatness is a good thing, and so if a mother is a little fat and is able
to consume a rich diet, it might make evolutionary sense for her to signal to her offspring that the opportunity to capitalize on this environment exists. If a mother were able to indicate to her offspring during its development that it should look out for fat and sugar, and gobble it up when it can, this might have an advantage for the fetus in terms of its later reproductive (that is, evolutionary) success.

It
might
, we stress, because obviously the kinds of diets and lifestyle we now have are novel in evolutionary terms, so this process would only operate up to a certain point, almost certainly exceeded by now. But it can explain why the babies of some obese women go on to become obese themselves.

This idea fits with the biology of many other animals, especially those that breed at different times of the year, where it is essential for the metabolism of the offspring to be set from the time of birth or hatching if they are to get the most out of their environment. And it fits with some of the biochemical changes which we have found in organs such as muscle and liver of the rat and mouse offspring of fat-fed mothers, which appear to be more those of exaggerated normal function than of pathological dysfunction but which favour fat deposition. At first this is not harmful, and in fact it is part of an effective life-course strategy to promote greater reproductive success. But given the nutritionally rich world that many babies are now born into, these mechanisms soon lead to too much fat being laid down and damage to blood vessels and other cells, which put the growing child at risk of chronic disease.

Explanations derived from evolutionary biology are rather satisfying, but in this case the idea cannot really be tested except by extrapolation from animals. It does have implications, however, which we
can
test. One is that the processes by which a mother signals to her growing fetus information about aspects of her environment, including how obesogenic her diet is, might be expected to interact with those regulating fetal growth through the mechanisms of maternal constraint, which we described in the last chapter.

Now we can take the idea further. If, at the other end of the dietary and body composition spectrum, aspects of the mother’s high-fat diet and adiposity are signalled to the fetus, then not only should the offspring of fatter women be more likely to become fatter as they grow up, but the first-born offspring of obese women should be the fattest of all as young adults. This is exactly what has been found in the Motherwell study that we described in the last chapter, where the first-born children, who were now adults, of obese women had a higher percentage of body fat than their later siblings. Importantly this interaction was seen across the entire range of levels of fatness in mothers from the thin to the obese—the fatter the mother, the fatter the offspring. There was no obvious cut-off in the level of maternal obesity at which pathology in the offspring sets in. This might argue that the toxic explanation we put forward earlier is less important than this evolutionary explanation. But either way, as so often in our story, we are in the territory of normal human biology within the normal range of human experiences, which is so overlooked and yet so important.

What about the father, though? If this theory about signalling nutritional states to the offspring is valid, could he not have a role too? Why leave it only to the mother to signal critical aspects of the environment to the offspring? One could expect the mother to have the dominant role, because mothers have a longer period of biological contact with their offspring during pregnancy and lactation, and because there were virtually no processes known by which the father could signal such things to his offspring anyway. His role was thought to be limited to what kinds of eating and lifestyle behaviours he might impart to his child as he or she grew up.

No one had really looked hard at this question until recently. But as we described briefly in the last chapter, a group from Australia has now shown that male rats that are fed to become obese sire offspring that have abnormal metabolic control as they grow up, regardless of the mother’s diet and fatness. This suggests that in some way a signal
is passed on in the sperm which influences the metabolism of the offspring. More than that we do not know at present—there is some data that epigenetic changes can be found in sperm and that these can influence the next generation. But whatever the mechanism, the implications for fathers-to-be are obvious. There is no room for complacency among males.

We are facing a new epidemic—diabetes in pregnancy—and it is emerging with horrifying speed, particularly in some parts of Asia. This is a special form of diabetes—it appears in pregnant women, but then disappears after pregnancy. It will come back in the next pregnancy and in time most of these women will go on to develop diabetes even when they are not pregnant. Just 15 years ago the incidence of this transient diabetes in pregnancy—we call it gestational diabetes—was only about 7 per cent in places like Singapore. This is a percentage not very different from what we see in countries like New Zealand and the UK. But now more than 20 per cent of pregnant women in Singapore have gestational diabetes. The same rapid increase is happening in Hong Kong and China, where at least 20 per cent of women in the richer big cities now develop diabetes during pregnancy.

Diabetes in pregnancy has consequences for both fetuses and babies. If it is very severe, the placenta can be damaged and the fetus become severely growth-impaired or even die. Lesser degrees of gestational diabetes tend to do the opposite—they cause the fetus to grow bigger and this can override the constraining mechanisms we discussed in the last chapter. The fetus will lay down more muscle and, especially, more fat in its body. This is because glucose crosses the placenta easily; it means that when mothers have diabetes, they have high blood sugar levels and so then does their fetus. This leads the fetus to make more insulin, which leads it to make more fat cells. And because the fetus is receiving excess energy in the form of
sugar, it then stores that excess energy as fat. The very biggest babies we see are those from diabetic mothers, and they can be so large that delivery is not possible without a Caesarean section.