Fat, Fate, and Disease : Why we are losing the war against obesity and chronic disease (6 page)

The foods we eat contain very many different kinds of fat—unsaturated or saturated fats, omega-3 or omega-6 fats, and so on. These different names refer to the biochemical structure of fat. The simplest form of fat consists essentially of a long chain of carbon atoms joined together with hydrogen and oxygen molecules attached. But not all fats are these simple lipids; some are joined to glycerol to form what are called triglycerides, which are made of a glycerol molecule attached to three fat molecules. Fats travel in the bloodstream from the liver, where they are first received after digestion or are made from other food types, to fat tissue. Or they can travel back to liver and muscle for burning. When fats travel in the bloodstream
they are attached to proteins called lipoproteins. It is the different levels of triglycerides and lipoproteins in a blood sample that doctors use to assess our fat status and one of the risk factors for disease.

Cholesterol is also biochemically related to fat and is often found in food in association with fats. Its structure consists of a set of rings made of carbon atoms. It is a much more complex molecule for our bodies to make, but the liver can produce it. We need cholesterol to make steroid hormones and for some other building blocks of our bodies. But we also consume cholesterol in our diet and, like its linear cousins, it can get deposited in our blood vessels and damage their functions or even block them. Blocked blood vessels in the brain cause strokes and in the heart they cause a heart attack.

There is increasing evidence that what we eat can change our body’s fat composition. For example, women who eat a lot of food containing omega-6 fats produce breast milk which has higher concentrations of omega-6 fats. Human milk, like animal milk, is fat-rich because this is the best way of providing the energy that the growing baby needs. Over the past 20 years the ratio of omega-6 to omega-3 fatty acids in human milk has doubled, reflecting the much higher intakes of omega-6 fatty acids in the modern Western diet. The biggest source of omega-6 fatty acids comes from cereal grains whereas omega-3 fatty acids are found in the highest concentration in fish oil. Similarly, depending on how much cholesterol we consume, we can change its levels in our blood. But because we also make cholesterol in our liver, people with dangerously high levels of cholesterol need to take drugs such as statins to reduce the risk of blood vessel damage.

Our focus so far has been on what we call white fat—this is the fat we are worried about because it is associated with the risk of cardiovascular disease and diabetes. But there is another kind, called brown fat. Newborn babies have much more of this fat than
adults. It is found around the kidneys, between the shoulder blades, and at the base of the neck. Even though adults have less brown fat, we may be able to increase the amount we have—for example, there is some evidence that exposure to cold can induce more to form.

Why is some fat brown, and why is this medically good fat? The colour difference is due to the fact that it contains many more mitochondria, the energy-producing factories of the cell. Mitochondria throughout the body generate the energy for the cells to work by burning fuels including fat. But we also need to generate heat, because we are a warm-blooded species and our biology is designed to work at a body temperature of 37 °C. That is the temperature at which our enzymes and body function have been optimized over evolutionary time. If our body temperature is too cold we do not cope well—death from hypothermia will occur if we cannot warm up. And we all know how awful we feel if we have a temperature which is too high. Heat is just a form of energy and all our cells contribute to generating it to keep us at 37 °C. But brown fat is particularly good at generating heat and that is why newborn babies have much more of it. One of the most important transitions from being a fetus to being a baby is to start controlling body temperature. Premature babies are much less efficient at maintaining their body temperature because they have less brown fat. For this reason we may have to keep them warm in an incubator to survive. Strangely, the incubator was first developed for showing off premature babies in sideshows, like circus freaks at the St Louis World’s Fair in 1904.

Brown fat produces more heat than white fat because its mitochondria have different settings. So rather than storing energy, these mitochondria produce heat. This is called ‘uncoupling’ and has been known in principle for many years, although its biochemical pathways in the mitochondria have only been described in detail in the past two decades.

One of the first observations of the function of brown fat arose during the First World War in women working in munitions factories in France. They were packing explosives into the shells used to bombard German
trenches so futilely and tragically in the Somme. The women were observed to be taking rather too much time off work. True, the conditions in the factories were fairly bad by today’s standards but there was a war on and Lord Kitchener’s finger, pointing directly at the viewer from behind his handlebar moustache on thousands of posters, made it clear that every citizen was expected to do his or her duty.

These factory workers said that they felt pretty sick and found it hard to come in to work. Some of them would start a day’s work but have to go home early. Were they really ill or just malingering? It seemed that they were ill because they certainly had high temperatures. Perhaps the crowded conditions of the factories were conducive to the spread of some infection. But if it was truly an infection, it was very nasty indeed and one that had not previously been encountered in medicine. Some workers developed temperatures which rose very rapidly during the day; they sweated profusely and began to shiver, and had to be taken to the sick room where colleagues covered them with blankets in the hope of stopping their shivering. But their temperature rose still higher and several of them died.

Clearly this situation could not be allowed to continue, for the sake of the war effort if not for the health of the munitions factory workers. Observation of the patterns of illness, associated as they were with the working day and only occurring in some workers in the factory, finally led to the answer. The workers were being continually exposed to the substance dinitrophenol, a key ingredient of the explosives packed into the shells. Dinitrophenol changes the biochemistry of mitochondria so that even those in white fat start burning fuel like brown fat—it uncouples mitochondrial metabolism so that energy is produced as heat rather than as metabolic energy.

We have already said that, except in cases of gross obesity such as those caused by genetic defects, simply being fat in itself does not
directly cause disease. But being fat changes our risk of getting disease. And it does so in several ways—some direct and some indirect.

While fats are essential to our body function and some are essential in our diet, excessive intakes of cholesterol and of some specific forms of fat are more likely to be harmful. For example infant milks are supplemented with the unsaturated omega-3 fat called DHA because we believe this is essential for brain development—indeed the brain depends on many special fats to function properly, and DHA is a type of fat which our bodies cannot efficiently make from other fats. But other fats may not be so healthy. Saturated fats are not as healthy as unsaturated fats. The membranes of cells are made from fatty molecules and if the diet is high in the wrong kind of fats the cell membrane composition changes and this in turn alters the way the cells function.

As our body levels of visceral fat increase we start depositing fat in the liver and muscle. We can see these effects even in some young people, using new medical imaging techniques. The fat deposited changes the way in which these organs work to regulate our metabolism. Again, one significant thing they do is interfere with the ability of insulin to work properly. When blood levels of cholesterol and fat are high, we even start to incorporate these molecules into the walls of our blood vessels and this leads to plaque formation—plaques are like scales on the inside of our blood vessels that interfere with their ordinary functioning and can form a focus for blood clots which can block the vessels. Blood vessels elsewhere can be affected; for example, fat-associated poor vascular function is an important reason for erectile failure in older men. The widely used drugs Viagra and Cialis work by opening the blood vessels up and sending blood to the penis, so it becomes more erect. Might this fact be marketed as an incentive for men to stay thin?

Because the wrong kind of fat in our cell membranes leads them to be stiffer, some hormones cannot do their jobs properly. Insulin made by the pancreas increases in the blood when blood glucose
levels rise, because it stimulates the entry of glucose into cells—particularly in the muscle and liver where it is used by mitochondria as a fuel source. Our bodies are designed to use glucose as the primary source of fuel, with fat as the backup—just as hybrid cars are designed to use the battery first and fuel as the backup. But if our cells are not sensitive to insulin, we cannot use glucose as a fuel and its levels in the blood rise. When they remain high for too long the glucose joins to proteins in all sorts of tissues including blood vessels, nerves, and the kidneys, impairing their functions. This is why the complications of diabetes include blood vessel disease, heart attacks and strokes, nerve problems, and kidney failure. The eye is particularly sensitive to high levels of glucose affecting its blood vessels, nerve cells, and the lens. This risk of blindness is high in poorly controlled diabetes. Indeed the longer we have diabetes the more likely these complications become. Treating diabetes well is not easy—it involves drugs which are variably effective or, if the disease is severe enough, insulin injections. Diabetes of this type can be very problematic for both patient and doctor.

As for insulin, when cell membranes become affected by the wrong fats, leptin does not work well either. Because leptin naturally suppresses appetite, this dysfunction might exacerbate the problems associated with a high-fat diet by reducing satiety. Furthermore there are complex feedback links between insulin and leptin secretion. Once these systems become disturbed by impaired responses to these hormones, the risk of disease rises.

But fat tissue is more than just fat cells. Visceral fat contains immune cells that make inflammation-causing substances. So someone who has more visceral fat is likely to have a greater inflammatory profile. Inflammation is the process by which cells similar to the white cells of blood invade tissues and secrete chemicals and hormones which can damage neighbouring tissue. Inflammation is good when it surrounds a wound and kills invading bacteria to prevent infection, but it is not good when it attacks otherwise healthy
tissue—for example our blood vessels or kidneys. The role of inflammation relative to the other mechanisms we have described in diabetes and cardiovascular disease is uncertain—but both are more likely if we have the wrong kind of obesity.

Obesity also leads to an increased risk of some cancers. It is not entirely clear why. Some hormones like oestrogen and progesterone are more soluble in fat than they are in water and so are found in greater concentrations in fat tissues. Hence fat can act as a store for these hormones and they can be metabolized inside fat into more active forms. This may explain why sex-hormone-sensitive cancers like post-menopausal breast cancer and uterine cancer are more common in obese women, although prostate cancer is not more common in obese men. But other cancers that are not obviously hormone sensitive are also more common in obese people, including kidney and colon cancer. Perhaps the answer to these differences in risk lies in changes in cellular response to growth hormones too—we need much more research here.

What we have described are ways in which obesity appears to lead directly to an increase in disease risk. But there are more indirect considerations we must not ignore. Obesity can be an indicator of other forms of unhealthy lifestyle and it may be that much of the disease risk associated with it results from these lifestyle factors.

Obesity may indicate an unhealthy diet, for example one high in so-called ‘trans-fats’. These are an unusual form of unsaturated fat which is not healthy because it changes the concentrations of fat-protein complexes, leading to higher levels of the unhealthy form of cholesterol (LDL) versus the healthy form (HDL). There are small amounts of trans-fats in some milk, and in red meat, but the majority of trans-fats in our diets come from chemically processed foods in which the fat has been changed to make it stable.

But it goes beyond that. Research shows that people who have poor diets are also more likely to smoke and less likely to seek early
medical advice if they become ill and it is sometimes difficult to determine which of these factors are most important, whether we are assessing cause or effect.

The ‘metabolic syndrome’ is the name given to the association between visceral obesity, unbalanced levels of fats in the bloodstream, and diabetes and cardiovascular disease. Not all elements need be present for someone to have the syndrome and indeed the relationship between them varies between individuals, both within and across populations. It is called a syndrome rather than a single disease because it is this collection of components which leads to the pathological condition and health risk to an individual. Sometimes the use of a word like ‘syndrome’ seems to be only a way of concealing our ignorance about what is really going on in a disease process. But while doctors and scientists argue about this in relation to the metabolic syndrome, it is becoming clear that in this case it is a set of health problems that often do go together. However, there may be one set of risk factors which leads to the syndrome in a particular person, and quite a different set in another person. This may make the problem hard to tackle, especially in terms of prevention, because the necessary measures will not be the same for everyone. This means that we have to look harder at the origins of the syndrome, and indeed of obesity itself. We will do this in the next chapter.