THE WORLD is facing an accelerating pandemic of obesity. In the UK alone about one thousand people die prematurely each week from obesity or its complications. Being obese doubles your chance of getting bowel and breast cancer and causes osteoarthritis, diabetes, hypertension and lung disease. And excessive eating raises levels of cholesterol, which accumulates in your arteries causing strokes and heart attacks.
Socially, too, obesity is a disaster. People who are overweight are depressed, they have a lower than average income, a higher divorce rate and commit suicide more often. Obesity is probably the single most important reason why, in spite of all the advances in medicine and sanitation, we are not living much longer than people a hundred years ago.
Why is this happening? Obesity is an almost inevitable result of our civilised environment. We humans are designed to gain weight during the good times to tide us over when there is no food. This tendency has its roots in our evolutionary past: people who didn鈥檛 fatten up during a good harvest died out in the subsequent famine, and we are the descendants of the survivors.
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Unfortunately, in our current environment food is freely available and the good times just keep on rolling. Society also conspires to prevent us burning off excess calories. A hundred years ago if you wanted to go somewhere you would walk. That sort of thing is now considered crazy.
The odd thing is that we are not fatter. Most people only maintain their weight by conscious and continuous restraint. Is there any alternative to a life of frugal eating? As a scientist my first thought is to work out what controls the appetite circuits in the brain. These are permanently set to cope with famine. Can we readjust them for an environment where food is plentiful?
Over the past few years we have learned a great deal about the biology of appetite. From knowing next to nothing in the early 1990s, we now have a fairly complete picture of the circuits in the brain and the mechanisms in the body that regulate hunger and body size. And these discoveries, I believe, are bringing us closer to the first effective 鈥渃ure鈥� for our natural tendency to overeat.
The big breakthrough came in the mid-1990s when an appetite-inhibiting hormone was isolated from fat. It was given the name leptin. Here at last was a concrete scientific mechanism for controlling body size. The more fat you have, the more leptin you make, and the more leptin you make the more your brain throttles back appetite. This seemed an amazing insight into the way the body regulates fat and led immediately to an attempt to use leptin as a therapy for obesity. It didn鈥檛 work. It turns out obese people already have very high leptin levels and injecting more makes little difference. In fact, overweight people are leptin-resistant 鈥� perhaps one of the reasons they are overweight in the first place.
We now feel that leptin is an unusual hormone. In fact it works rather like a vitamin 鈥� you have to have a certain amount of it, but more of it doesn鈥檛 make any difference. Without leptin you become ravenously hungry, but as soon as you have some your appetite returns to normal.
The story of leptin, however, did illustrate that the body regulates appetite the same way it does everything else 鈥� by hormonal and neural mechanisms. And thanks to leptin research we now have a fairly complete picture of how those mechanisms work, and some tantalising clues about how to halt obesity.
Leptin acts primarily on two opposing sets of appetite-regulating neurons in the brain. It triggers an appetite-inhibiting circuit and shuts down an appetite-stimulatory one, with the net effect of damping down your desire to eat. The two circuits lie side by side in the arcuate nucleus in the base of the hypothalamus and send signals to the paraventricular nucleus or PVN, which is responsible for regulating eating behaviour. This system exerts exquisitely fine control over how much you eat (see Diagram).
Here鈥檚 how it works. When the stimulatory circuit is activated it pumps out two neurotransmitters, both of which promote eating. One, called neuropeptide Y (NPY), sends a direct 鈥渆at鈥� signal to the PVN. When injected into the brains of animals NPY makes them eat voraciously. The other, called agouti-related peptide (AgRP), operates more subtly, blocking an appetite-inhibiting switch in the PVN called the melanocortin type 4 (MC4) receptor.
The inhibitory neuron also works via the MC4 receptor. When activated, it pumps out a neurotransmitter called 伪-MSH (melanocyte stimulating hormone) that switches on the receptor and damps down appetite.
This circuitry was worked out by looking at leptin, a long-term regulator of energy balance. Our own research, though, focused on a slightly different problem: why do you lose your appetite after a meal? No matter how ravenous you are before you eat, afterwards you become uninterested in food. What produces this tremendous difference?
There are a number of possible mechanisms. For example, it might be the distension of your stomach that makes you lose your appetite. But when we give people a meal of non-nutritious bulk, boiled cabbage for example, they feel frustratingly distended but still hungry. We also know from hospital patients that intravenous feeding has little effect on appetite.
So what does explain the loss of appetite after a meal? We鈥檙e left with two possible mechanisms. One is the nerves that run from the gut to the brain. The other is the hormones produced in the gut which reach the brain via the bloodstream. Our own research has focused on the hormonal aspects of appetite control, and two hormones in particular: one from the stomach called ghrelin, and one from the intestine called PYY3-36.
Ghrelin is a small peptide made in endocrine cells in the stomach. It is a very potent stimulator of food intake in animals: injecting it directly into the brain or into the bloodstream causes dramatic eating. Ghrelin levels are high when you鈥檙e fasting and fall after you have eaten. So here we have a hormone that stimulates appetite, comes from the stomach and is high in the circulation when you haven鈥檛 eaten. The obvious experiment to do, which we did in human volunteers at the Hammersmith Hospital in London two years ago, was to infuse ghrelin into the bloodstream to maintain the high fasting level even while eating a meal.
On some days we gave the volunteers ghrelin, and on the other days saline. Nobody knew which was which until after the experiment. Then we found that the volunteers ate much more on the days they got ghrelin than on the saline days, about 30 per cent more. We asked them if they could tell which substance they were getting and they couldn鈥檛 鈥� there were no side effects attributable to the ghrelin infusion. So ghrelin is truly a hormone of hunger.
The second hormone, PYY3-36, comes from the small and large intestine. It is low on fasting and rises after a meal. We found that this hormone is a potent inhibitor of appetite in animals when injected into the bloodstream. It also selectively inhibits the appetite-stimulating neurons by binding to a receptor called NPY Y2. PYY3-36 does not inhibit food intake in mice lacking this receptor. So it looks as though PYY3-36 is the hormone of satiety, which switches off the appetite stimulatory circuit in the brain.
After the rat experiments we obviously wanted to know what effect the hormone would have on humans. We did another experiment with volunteers, infusing PYY3-36 in a dose adjusted to mimic the rise after a meal. This time the subjects on the hormone ate about 33 per cent less. As with ghrelin, there were no side effects and the volunteers couldn鈥檛 tell whether they were getting the hormone or not. Interestingly the effects persisted for a full 24 hours, so that people who had PYY3-36 the day before ate less at breakfast the next day. This fits with our understanding of what normally happens after you have eaten a very big meal: you don鈥檛 feel as hungry the next day either.
And the more calories you eat the bigger the rise in PYY3-36. Slowly digested food, such as fat, gives a bigger rise, as do fibrous foods. Perhaps our refined carbohydrate diet may diminish the PYY3-36 response, and trigger overeating.
We also wondered whether fat people had an altered PYY3-36 system and in preliminary studies found they reacted normally to its effects, but had a rather small release when eating a standard meal. A deficiency in PYY3-36 might explain their excessive appetite.
We now have two hormones to play with, ghrelin, the hormone of hunger, and PYY3-36, the hormone of satiety. How and where do these two hormones work? To discover the mechanisms we turned to a trick that tells us when a neuron has been switched on. Any recently activated neuron always ramps up the action of a particular housekeeping gene called c-fos. Thus, using the production of high amounts of c-Fos protein as a marker, we found that both ghrelin and PYY3-36 were activating neurons in the arcuate nucleus 鈥� the exact site of the hunger circuitry controlled by leptin.
Ghrelin switches on the stimulatory neurons, the ones that make you eat, and switches off the inhibitory neurons. PYY3-36 has the opposite effect. And so we have a beautiful system in which the gut produces a set of signals that act on the appetite control systems in the brain.
How does this help us in our quest for an obesity 鈥渃ure鈥�? Crucially, it gives us a clue on how to reduce appetite artificially without side effects. And this is one area of medicine where absence of side effects is an absolute must. Patients might start taking an appetite-reduction pill when they are 15 and carry on taking it until they die at the ripe old age of 85. That pill better have no side effects.
Theoretically there are four approaches to treating obesity with drugs 鈥� but so far nothing has been developed that has no side effects. Certainly, there is no effective tablet on the market to help you lose weight, and in fact, the approaches big pharma has taken might well be intrinsically flawed.
The first approach is to stop the amount of nourishment the body is absorbing, epitomised by products such as fat-free yogurts. Swiss pharmaceutical company Hoffmann-La Roche markets a compound, Xenical, which blocks gut lipase and so prevents you from digesting fat. But many people won鈥檛 take the drug because this undigested fat can cause unpleasant bowel problems such as anal leakage.
The second approach is to increase energy expenditure. It is well known that the hormone thyroxine makes you overactive. People whose thyroid gland produces too much thyroxine run up and down, sweat a lot, eat plenty and are very thin. So you might think that thyroxine is a useful way of keeping your weight down. The bad news is that thyroxine influences general metabolism in a harmful way and can lead to heart problems. Other drugs developed to influence energy expenditure have also proved to be toxic.
The third approach is to target fat itself. There are various agents that alter the way in which fat is metabolised and make it melt away. This sounds ideal, but again drugs which interfere with fat metabolism also affect very basic functions of the body and may well not be safe in the long term 鈥� though scientists hope to develop something safe eventually (快猫短视频, 23 March 2002, p 28).
The final approach is to regulate appetite. The pharmaceutical industry has put an enormous amount of effort into finding agents that will either switch on or switch off the appetite circuits in the brain. But there is a major problem with this approach. These appetite circuits use certain neurotransmitters, but neurotransmitters are rarely specific 鈥� NPY, for example, is found throughout the brain and has many different functions. A drug that blocked the effects of NPY would certainly reduce appetite, but it would also have an affect on other areas of the brain, and so would be liable to produce long-term side effects.
The same is true of most of the other appetite suppressants the pharmaceutical companies are developing. For example, French company Sanofi-Synth茅labo has a cannabinoid-receptor-1 antagonist in clinical trials. It reduces appetite, but will certainly affect cannabinoid receptors throughout the brain, which have multiple functions. Another company has produced an analogue of a peptide called CNTF (ciliary neurotrophic factor) which is important in activating certain immune effects. One of these is reducing appetite 鈥� people frequently lose their appetite when fighting an infection. But the drug will probably have all sorts of other effects on the immune system. Another approach is to use mimics of the natural appetite inhibitor a-MSH. These greatly reduce appetite but also influence the sexual functioning of the brain with some very interesting effects.
Our research, though, suggests there is a safe and effective method 鈥� exploit the natural way in which hunger is controlled on a daily basis. Every time you eat a meal you lose your appetite. So our proposal is to fool the body into thinking it has eaten by artificially administering the hormones that your body releases after a meal. We intend to try and show that by giving PYY3-36 to overweight human volunteers we can help them control their appetite.
One problem is that, like insulin, PYY3-36 is a peptide and so must be given by injection to prevent it being digested. We now have to find a way of giving people an injection every day 鈥� we are copying insulin administration to diabetics. This may make it a treatment that is only suitable for the seriously overweight. But it is a practical approach to reducing appetite with a hormone you release naturally after every meal, so it is unlikely to be harmful or lose its effect after many doses. Maybe, just maybe, we finally have a safe and effective treatment for obesity.
