Why We Eat (Too Much) Page 11

  Leptin levels tell us whether to go out looking for food or to go out looking for a mate. Basically, leptin enables your fat stores to speak to your brain, letting it know how much energy we have stored and, most importantly, what to do with this energy.

  The word ‘leptin’ derives from the Greek leptos, meaning ‘thin’. Leptin, when it is working properly, will do just this – make you thinner. When the fat–brain axis is functioning correctly, a person will be able to relatively easily maintain a stable body weight over a long period of time without any type of conscious control of calorie intake or any need for extra energy expenditure in the gym. All this is down to leptin – our powerful metabolic thermostat. By directing energy in as well as energy out, leptin exerts long-term control over our energy reserves. The leptin signal means that our energy stores are able to self-regulate in a classic biological negative feedback loop.

  When leptin is high, food is off the brain’s agenda and we are free to daydream about other things. In addition, via stimulation of the sympathetic nervous system, leptin increases our metabolism, meaning that seamlessly, without any effort, we burn off excess energy without even having to get out of our chair.3 When leptin is working, it is a wonderful hormone to get our weight back down to where the subconscious brain wants it to be – down to its set-point.

  Some people, who can keep their weight stable for years, may congratulate themselves that they are able to consciously control their holiday weight gain of a few pounds by sweating it off at the gym after their return, and maybe also by calorie-counting for a while. But, in actual fact, leptin is the boss. High post-holiday leptin levels, caused both by weight gain and by over-eating, will lead to a much higher level of metabolic energy expenditure per day than any half-hour jog, effortlessly. The post-holiday diet to get the excess pounds off is aided by leptin cutting off appetite and food desire. The diet seems easy and the exercise works better than expected: normal weight is regained (Figure 4.3). If you fight the battle with leptin on your side you will win easily, but even without conscious effort your weight would have eventually settled down towards your original set-point anyway; it would just have taken slightly longer.

  Figure 4.3 How the action of leptin aids a reduction to the weight set-point

  Figure 4.4 How leptin can act to cancel out weight loss through dieting

  In a similar way to excess holiday weight coming off more easily than expected, thanks to our leptin thermostat, we can also explain the difficulty of continued weight loss on a low-calorie diet. Remember, leptin is the master controller of our energy stores. If these stores differ from what our subconscious brain perceives to be the safest weight, i.e. our own personal weight set-point, leptin will act to correct the difference. If our weight falls below our weight set-point (this is usually because we are trying to lose weight by consciously dieting), then leptin levels fall, as fat is lost. The effect of this? Plummeting metabolic rate and a voracious appetite. We may win a short-term battle, but leptin will always win the war between our conscious and subconscious will to eventually return the body to the desired weight set-point (Figure 4.4).

  Leptin was discovered in 1994 by researchers at the Howard Hughes Medical Institute, Rockefeller University, New York. The scientific team, led by Jeffrey M. Friedman, discovered a way to breed mice that were unable to make leptin.4 As the mice lacked the leptin-making gene, their fat cells could not manufacture it. They compared these mice to normal mice and found that the leptin-deficient ones developed a voracious appetite and exhibited massive weight gain. Despite being fed the same types of food, the mice which had no leptin in their bloodstream were soon double the size of their neighbours. Even when they were clearly struggling with severe obesity, these mice still exhibited the behaviour of a ravenously starving animal. Although they now had enormous fat reserves, their fat tissue was unable to produce leptin, which led their brains to assume the ‘petrol tank gauge’ read zero even though the ‘tank’ was overflowing.

  When the researchers injected the leptin-deficient mice with a leptin replacement, their behaviour suddenly changed. They no longer ate voraciously and seemed to have more energy. After a series of leptin injections, the rats eventually lost all the excess fat that they had gained – and their obesity was cured.

  Researchers at the University of Cambridge were the first to discover a similar genetic deficiency of leptin in humans. In 1997 Dr Sadaf Farooqi and her team in the Metabolic Disease Unit investigated two cousins of Pakistan origin who had extreme early-onset obesity.5 The cousins, both girls, were aged eight and two. They’d had normal birth weights but both had exhibited a constant ravenous hunger thereafter. If food was denied them, they would develop severe behavioural disturbances with tantrums and violent mood swings. The elder cousin had already undergone liposuction before the age of eight, but to no effect, she weighed 86kg (13 stone 7lb). Her two-year-old cousin already tipped the scales at 29kg (4 stone 7lb). When the team of researchers tested their leptin levels they found that despite their having massively excessive weight, and fat reserves, they had almost no leptin in their bloodstream. The signal to the rest of the body that their fat stores were excessive was absent. In fact, the opposite was the case: the extremely low levels of leptin were a strong signal to the body that energy stores were critically low. The cousins’ aggressive voracious eating behaviour was a normal response to this perceived mortal danger of starvation.

  The next step for the Cambridge researchers was to mirror the successful treatment of leptin deficiency that had been reported in the original study of genetically leptin-deficient mice. The cousins began a series of leptin-replacement injections. Immediately, just as in the animal studies, their behaviour changed, their appetite decreased and they started to lose considerable amounts of weight.

  These were exciting times for obesity research scientists around the world. There was hope that finally, after years of effort, the definitive cure for obesity had been found. It was assumed that leptin, when injected into obese people, would cure them of the condition. Pharmaceutical companies and their chief researcher scientists jostled for position to be able to own this product. Massive amounts of money were at stake. This would be the trillion-dollar drug they had been looking for.

  But then the results of the scientific studies started to be published. Several different research groups tried, and failed, to produce weight loss in obese humans by injecting them with leptin.6 They measured the leptin levels of their obese subjects and found they were elevated, and yet the leptin signal did not seem to be getting through to the appetite- and metabolism-controlling centres in the brain. In fact, when compared to a placebo treatment (water instead of leptin), there was no difference in weight loss.

  What was the difference between the successful treatment of genetic obesity in the young cousins – and also in the leptin-deficient mice experiments – compared to the failure of treatment in subsequent human trials? When the researchers looked at the leptin profiles of a normal obese person in the human trials they found that their leptin levels were high, reflecting their level of obesity. These people had gradually put on weight throughout their lives, compared to the Pakistani cousins who had voraciously eaten since birth and put on weight rapidly. The cousins had very low, almost zero levels of leptin, while the obese adults tended to have high levels of leptin. It soon became apparent that inherited genetic disorders causing low leptin levels were extremely rare. In fact, after the discovery of the leptin-deficient cousins, only fifteen similar cases in the whole world have subsequently been identified. The genetic mutation to cause leptin deficiency needs to be transmitted from both the mother’s and father’s genes. As these mutations are extremely rare, they tend only to appear in consanguineous relationships where close families intermarry.

  The next question we need to examine is how could someone become obese in the presence of high levels of leptin? This seems to be the norm in most people suffering with severe obesity. What has gone wrong with leptin, o
ur powerful fat controller? The next chapter explains why the master regulator of our weight can stop working.

  Summary

  We have learned in this chapter that our appetite (that uncontrollable urge to eat) and our feeling of satiety (that feeling that sufficient food has been taken in) are strongly controlled by newly discovered hormones that originate in our stomach and our intestines. The stomach hormone, ghrelin, tells us to go out and seek food – it’s the signal to take in energy in the form of food. The hormone peptide-YY, originating in the intestines, sends us the message to stop eating – we know we have had enough food for now.

  These hormonal signals are extremely powerful: appetite can be like a parching thirst and strong feelings of satiety can make you feel nauseous. They are designed to be part of that negative feedback loop – trying to keep our weight at the brain’s perceived safe weight set-point. Lose too much and you will be ravenous and never feel full. Gain too much and you will lose your strong appetite and feel satisfied without food. In the fight for your weight your subconscious brain will always win – forcing you to take in the energy that it wants.

  When combined with the dramatic decrease in our metabolism (energy expenditure) that can occur to stop weight loss (as discussed in the last chapter), it should be becoming clear that the old-school weight-loss equation – energy in (food) – energy out (metabolism) = energy stored (fat) – is not under our conscious control.

  We learned that bariatric surgery works by dramatically altering the appetite and satiety signals from the stomach and small intestine to produce seemingly effortless weight loss. People who have undergone this type of surgery are relieved that their appetite was not really part of some sort of character flaw – that it was not in fact under their control at all.

  Finally, we learned that leptin, the hormone produced by our fat cells, is the master controller of our weight. It works to stop us getting too fat by telling the brain how much energy is already stored – by acting in the same way as the petrol gauge on a car. Too much leptin means little appetite and a high metabolism – producing weight adjustment back down to the set-point. It helps direct both metabolism and appetite/satiety to keep our energy reserves on an even keel, preventing runaway weight gain and weight loss. In many people leptin is the reason that their weight is not an issue. They don’t count the calories as leptin is in charge. When this hormone is deficient, as occurs in a very rare genetic condition, staggering and rapid weight gain occurs.

  But if leptin is really the master controller of our weight, then why do people who suffer with obesity have such high levels seeping into their bloodstream from their fat? Why does leptin not seem to be working for them?

  The next chapter explains why the master regulator of our weight can stop working.

  FIVE

  The Glutton

  Understanding the Fatness Hormone

  As I sat down for breakfast, I took a moment to look around me. I was in Dubai for my clinics and the sun burned down on the terrace outside – the city and the Burj Khalifa tower shimmering in the distance. The murmur of morning conversations and the chink of cutlery filled the hotel’s dining area, with couples and families and singles enjoying the sumptuous buffet. I poured my tea, but was interrupted when I sensed a momentary silence in the atmosphere. I looked up and paused – the diners were gazing at a gigantic man who’d just entered. He was dressed in a traditional white Arab kandura robe, this one presumably specially made for him as it was as wide as it was long. He wore no headdress and I guessed from his hairline and the scattered grey in his stubble that he was in his forties. He moved well in spite of his massive size and round shape, but as he sat down at a table opposite me I noticed desperation in his eyes. He looked pale and was sweating profusely despite the cooling air-con. He was not a tall man but must have weighed 200kg (over 31 stone). He was breathless, though trying to hide it – and he looked as if he was really suffering.

  I covertly observed this poor man for the next hour as I ordered refills of tea. His behaviour was remarkable. He went to every station in the buffet and ordered the waiter to take each plate that he filled to his table. Eggs, hash browns, chicken sausages and beans piled on one plate, cold meats and cheeses on another; a large bowl of fruit cocktail was filled to the brim; Arabic flat bread and hummus, toast and jam; two plates piled high with cakes and croissants; and three large glasses of fruit juice. When he finally sat down ready to start breakfast, his table (which would normally seat four) was totally covered with plates of food, enough to feed ten people for breakfast. He ate extremely efficiently and very fast, but there was still desperation in his eyes. Within twenty minutes he had consumed the entire table of food. He ushered the waiter over for more …

  When the man had finally finished, he dusted himself down, raised himself out of his chair and walked confidently out. He looked much better in himself, his colour had returned and the haunted look had left his eyes. But I was left wondering how could one man eat so much and so fast? Was he greedy or had he become somehow addicted to food? Or was there something else going on – was his gluttony a symptom of an underlying disease?

  As for my fellow diners, who muttered comments to each other as he left, their views were obvious. Their subtle, out-of-his-view shakes of the head and empathetic glances towards each other told me their verdict. This man was guilty as charged. He was fat because he ate too much and he ate too much because he was a glutton. He had committed one of the seven deadly sins in full public view and showed no remorse.

  But what if reality were different? Let’s look at things from the man’s perspective. If we had asked him how he felt that morning, he may have told us that he had had a fitful night’s sleep, probably waking every hour as his body struggled to get oxygen into his system through his loud snores. Because of the low oxygen levels in his brain he would have described waking with a headache. As he got ready for the day, he would have been aware of a constant level of stress and anxiety on account of the way he looked and the way other people perceived him. But the main thing he would have remembered about that morning, apart from the headache and anxiety, would have been his ravenous hunger, the feeling that he had not eaten for a week, despite the fact that he binged on food every day. That’s why he looked so anxious and pale when he entered the dining area. Maybe hunger signals were driving his behaviour?

  But surely this man would have had an excessive amount of leptin in his bloodstream? Leptin levels should rise with increasing levels of fat. This should have had the effect of decreasing his appetite and increasing his metabolism. So, what had gone wrong with the feedback mechanism that was supposed to stop this poor man getting so obese?

  If we had measured his leptin levels, we would have been able to confirm that they were appropriate to the amount of fat that he was carrying: they were sky-high. So why is leptin, the hormone that controls fat storage month by month and year by year, not working? The answer to this leads us to the root cause of the disease of obesity. The clue comes from the studies of obese human volunteers who failed to lose weight when injected with leptin. In the experiment, leptin levels were high prior to the injections. Increasing an already high leptin level therefore had zero effect. Leptin did not seem to be working any more.

  In the Pakistani cousins who had a rare genetic leptin deficiency (see p. 87), the injections had a dramatic effect, enabling them to lose considerable amounts of weight. Leptin seemed to work appropriately when the levels in the body were low, but when the levels were high, it stopped working.

  The scientists concluded that at high levels leptin’s message to the brain starts to get disrupted. High levels of leptin are present, but the brain can’t sense this. When leptin reaches this threshold, a condition called leptin resistance develops. The brain is ‘blind’ to the high leptin levels and therefore to the high fat reserves. In fact, the opposite message is getting through: the brain senses a much lower leptin level than is actually present and interprets this as starvation st
atus. As we observed at the Dubai breakfast buffet, this can lead to increasing hunger and a voracious desire to stave off starvation. The effect? More weight gain, more fat-producing leptin, even higher leptin levels and even more leptin resistance. The fatter the man becomes, the hungrier he feels; the more he binges on food, the fatter he becomes. This vicious cycle of increasing weight gain and increasing leptin resistance, leading to more weight gain, describes end-stage, fully fledged obesity.

  Let’s go back to our petrol tank analogy. Imagine that you are driving your car and you notice that the fuel gauge is dangerously low. You immediately start to worry about finding the next petrol station. You need to fill up as soon as possible – it’s urgent. Little do you know that in fact you have a full tank of petrol. The problem is the fuel gauge – it’s broken. This is the same as leptin resistance – the brain thinks there is no fuel (fat) on board, but in fact there are plentiful reserves.

  The Tipping Point – Leptin Resistance

  The holy grail for obesity research is understanding, and then fixing, leptin resistance. If this can indeed be reversed, if the brain is able to recognize the high levels of leptin present, then it could correct itself. Triggering this change would mean sufferers’ voracious appetites and low metabolisms could be reversed and their weight would normalize – to continue the analogy, the broken fuel gauge would be fixed and there would be no need for unnecessary emergency stops at the petrol station.

  A clue to leptin resistance comes from our emerging understanding that it not only controls the amount of energy we store, but also tells us what to do with those energy reserves. Our DNA wants two things from us: survival and reproduction. Once we have reached adulthood our reproductive success is dependent on our nutritional status. If a young woman is not carrying enough fat, or energy reserves, then there is a risk that a pregnancy may not progress if food becomes scarce. If there are abundant fat reserves, then it is much more likely that a pregnancy will be successful, even if a food shortage has occurred. It therefore makes evolutionary sense that leptin, the fat messenger to the brain, only stimulates reproductive behaviour at times when it is nutritionally appropriate. This has in fact been confirmed in the research.1 Leptin, acting via an intermediary messenger, stimulates gonadotropin-releasing hormone (GnRH), which goes on to tell the ovaries to start functioning. An interesting side effect of the obesity that I see in many patients is a condition called polycystic ovary syndrome (PCOS), in which the ovaries stop functioning normally and the patient becomes less fertile. It may be that in the future we find that leptin resistance is contributing to this condition.