Although a number of the study participants had regained their weight, there was also an important clue as to why they'd had this so-called 'yo-yo effect'. These people presented with a particular physiological signature. It wasn't simply the food they ate. It mostly had to do with hormones.
Although these participants' 'fat thermostats' were turned on full blast, they were malfunctioning, no longer offering the brain the right information about food (J Clin Endocrinol Metab, 2010; 95: 5037-44).
What the Spanish researchers discovered in those who'd gained back their weight was higher levels of a hormone called 'leptin' and lower levels of another hormone called 'ghrelin', causing the researchers to conclude that these 'appetite-related' hormones may play an important role in weight regain after dieting.
Both hormones, discovered only in the 1990s, are agents that regulate appetite and fat levels. Leptin-which is made in our stored fat cells, or 'adi-pose tissue' stores-is, in fact, a protein hormone that circulates through the blood-stream as a signal to the brain as to your body's level of fuel and whether it's providing an adequate amount of energy.
Whenever you finish a meal, leptin is released from your fat stores and enters your blood-stream, eventually making its way to your brain to deliver the message that you are full, and that you have a certain amount of energy available.
In effect, rather than a thermostat, leptin could more properly be called an 'adipostat'-a fat regulator. It keeps your brain clued in as to whether you are hungry and how much fat is currently in your body, much as the gauge in your car lets you know how much petrol you have left in the tank.
As Robert H. Lustig-professor of pediatics at the University of California at San Francisco and an expert in obesity-puts it, leptin isn't a fat hormone, it's a 'starvation hormone', made to signal the brain when we need to eat more.
When leptin levels rise, your appetite tails off and you feel full. Your metabolic rate also increases. Your brain thinks you have enough food and fat to go about your normal bodily business. This, in turn, returns leptin levels back to normal. At that point, food loses its appeal and doesn't taste as good to help signal that you've had enough.
This process also sets your body's metabolism to normal, allowing you to eat normal amounts of food, and clearing the path for the body to under-go complex and energy-hungry processes such as puberty and pregnancy.
When you go on a diet and lose fat, you naturally produce less circulating leptin. Consequently, when your levels of leptin fall below a certain amount, your brain thinks you are starving and launches a number of initiatives to bring about a return to energy homeostasis (balance). One of the most basic of these actions is stimulation of the vagus nerve-the nerve that runs from the brain to the abdomen and governs energy storage-which will cause your appetite to increase.
During dieting, we are often in a leptin-deficient state. In one small-scale study, researchers using functional magnetic resonance imaging (fMRI) scanners demonstrated that obese volunteers who'd lost 10 per cent of their body weight also showed changes in neural activity all over the brain in response to visual food cues, indicating a state of leptin deficiency (J Clin Invest, 2008; 118: 2583-91).
Leptin also regulates the rate at which fat is broken down. As leptin levels rise, your fat metabolic rate increases. When you diet and your leptin levels fall, so does the metabolic rate. This is often why dieters reach a plateau in their weight loss: the body believes that it's starving and so is put on a kind of emergency alert, slowing down all physiological processes to maximize what energy it has.
Besides leptin, another important hormone for fat regulation is an agent that goes by the strange name of 'ghrelin'. This gastric amino-acid peptide stimulates the secretion of growth hormone and increases the amount of fat in the body, hence its name; 'ghre' is an Indo-European prefix for the word 'grow', and was presumably chosen by its Japanese discoverers in reference to its role as a growth-hormone-releasing peptide.
Leptin's opposite number
Produced in the cells lining the stomach, ghrelin is leptin's opposite number: levels of this hormone increase before meals and decrease after meals. Ghrelin affects a receptor in the pituitary gland-the so-called master gland of the body located at the base of the brain near the hypothalamus-that indicates the secretion of growth hormone from the anterior lobe of the pituitary to stimulate growth.
Ghrelin thus stimulates the release of growth hormone by acting directly on the pituitary, but it also affects various parts of the nervous system within the hypothalamus that are involved in appetite control.
As such, it appears to be centrally involved in the regulation of energy in the body. Indeed, the higher our levels of ghrelin, the hungrier we feel. Ghrelin levels peak before meals and plummet afterwards.
Although scientists have been using growth hormone for 25 years now, ghrelin was only discovered in the late 1990s, and its physiological role is still not clearly understood. In one animal study, ghrelin injected into rats rapidly stimulated their feeding behaviour and increased weight gain (Nature, 2001; 409: 194-8).
Consequently, although we know that ghrelin plays a major part in growth regulation by stimulation of feeding and growth-hormone release, the precise nature of the role is still elusive.
In one small-scale clinical study, the researchers used a crossover design. In this case, they first gave intravenous infusions of ghrelin to nine healthy volunteers and asked them to select food from a buffet.
Then, the experiment was repeated but, this time, they administered an intravenous infusion of saline, or salt water. The results showed that the volunteers clearly consumed more food when given ghrelin than when given the salt water, and also scored higher on appetite tests (J Clin Endocrinol Metab, 2001; 86: 5992).
Scientists have also observed that chronically obese people have far lower levels of ghrelin than do those who are of normal weight. Further-more, levels of ghrelin appear to be linked to circadian rhythms-and these are faulty in obese individuals (Proc Natl Acad Sci U S A, 2004; 101: 10434-9). Indeed, chronic sleep depriva-tion increases the production of ghrelin and, thus, also stimu-lates the appetite (see box, page 13).
However, there appears to be a subtle and possibly even competitive interplay between ghrelin and leptin in the regulation of appetite that, as yet, we do not understand. For example, in the rat experiment mentioned above, the injected ghrelin also blocked the reduction of feeding behaviour induced by leptin (Nature, 2001; 409: 194-8).
Overweight people such as those in the Spanish study who'd regained their weight loss have a problem that's referred to as 'leptin resistance'. Similar to 'insulin resistance' in type 2 diabetics, where the pancreas produces large amounts of insulin that the body can no longer deal with properly, leptin resistance occurs when increased levels of circulating leptin are no longer recognized by the brain.
In this scenario, there are loads of leptin and stored fat, but the brain believes that leptin levels are low. This leads the brain to think that the body is starving and, so, it stimulates processes to create a feeling of hunger, regardless of how much stored fat there is. Moreover, food tastes even better than it ordinarily does, which means that even more of it is eaten.
In the Spanish study, the group that regained more than 10 per cent of their weight had circulating leptin levels that remained higher than those of the other participants. Interestingly, however, those who'd regained the weight did not have higher levels of insulin, suggesting that it's leptin resistance, rather than insulin resistance, that most con-tributes to weight gain.
Recently, scientists at Harvard Medical School have found that leptin resistance is caused by scrambling of the endoplasmic reticulum (ER)- the protein-making part of the brain cells that produces them, folds them and returns them to the cells.
According to Umut Ozcan, a researcher at Children's Hospital Boston, when this protein production becomes faulty-a condition known as 'ER stress'-the brain grows 'deaf' to leptin signalling, resulting in a slowing down of protein production.
In earlier researches, Ozcan found that ER stress was linked to type 2 diabetes and insulin resistance. In animal studies, mice fed a high-fat diet developed signs of ER stress in the hypothalamus, the primary region of the brain that receives signalling from leptin (Science, 2004; 306: 457-61).
In yet another study by Ozcan and his team, a protein was removed from the hypo-thalamus of normal mice. ER function then went awry and the mice began to suffer from ER stress, becoming severely leptin-resistant and obese when fed a high-fat diet (Cell Metab-olism, 2009; 9: 35-51) .
As Ozcan puts it, "Most humans who are obese have leptin resistance. Leptin goes to the brain and knocks on the door, but inside, the person is deaf."
According to Tamas Horvath, a neuroscientist at Yale University who is studying the role of leptin in the brain, as the ER is the primary site of construction in the cell, the increased leptin signalling is akin to having architectural instructions to 'overbuild' to the point that the ER is eventually overwhelmed by having too many jobs to do at once.
Leptin also has an important role in maintaining adequate levels of fat in the female body and, consequently, this may indicate that women are more prone to leptin resistance. In fact, in the Spanish study, more women than men who'd regained their weight had high levels of leptin. Medicine now believes that women need adequate levels of leptin to maintain fertility.
Leptin also plays a vital role in initiating puberty (Pediatrics, 2008; 121: S208-17), and having abnormal levels may be related to type 1 diabetes (J Clin Endo-crinol Metab, 2001; 86: 1188-93).
Faulty leptin signalling also causes chronic inflammation in the body, which can eventually lead to cardiovascular disease and a host of other problems. It may also play a role in the development of melanomas or skin cancer, and is also thought to be, together with obesity, the most predictive marker of insulin resistance in children (Int J Obes Relat Metab Disord, 2000; 24: 1265-71).
Low levels of ghrelin
As with leptin, levels of ghrelin are abnormal in the obese. One study found that circulating levels of ghrelin were lower in the chronically obese in two culturally different populations compared with normal-weight individuals, suggesting that ghrelin is down-regulated in obesity, possibly due to the accompanying higher-than-normal levels of insulin and leptin. For this reason, the researchers proposed that these lower levels might represent some sort of physiological 'adaptation' to the body's constant oversupply of energy through excess food consumption (Diabetes, 2001; 50: 707-9).
While dieting, the body often produces more ghrelin than normal, as if the body, sensing that it's starving, is attempting to gain back the weight lost. In this study, the dieters were also compared with individuals who had undergone gastric bypass (bariatric) surgery; the results showed that the latter patients had markedly suppressed ghre-lin levels, which most likely contributed to any subsequent weight loss in the recipients of such a procedure (N Engl J Med, 2002; 346: 1623-30).
Nevertheless, the chronically obese may have a chronic deficiency of ghrelin-resulting in a feeling of never being full. Again, in the Spanish study, although those who initially lost weight showed no evidence of any changes in ghrelin, the ones who regained their weight were found to have lower levels of ghrelin than the others.
Furthermore, men had the biggest changes in ghrelin levels, suggesting that this hormone plays a bigger role in appetite control in men than in women.
Although leptin supple-ments are sold on the Internet as miracle weight-loss pills, leptin itself cannot be taken by mouth as a supplement because it's a protein and, as such, it would simply be broken down by the body as if you were eating a piece of chicken. In fact, most 'leptin' supplements are composed of a grab-bag of other supplements known to boost thyroid or leptin pro-duction, or to generate a feeling of fullness, such as soluble fibre.
Recently, conventional medicine-with its 'pill for every ill' mentality-considered leptin regulation as just a matter of taking a new pill (see box, page 11). However, the latest evidence suggests that both leptin and leptin resistance are controlled by lifestyle-in other words, what you eat, how much you exercise, how well you sleep and whether you are able to keep everyday stress in check (see box above and box on page 13). Even more important is the fact that leptin resistance is triggered by inflammation of the immune system-which, again, may be caused by an unhealthy lifestyle and chronic deficiency of omega-3 fatty acids.
In the end, the interrelation-ship between leptin, ghrelin, insulin manufacture and other hormone regulation in the body is highly complex and inter-twined, suggesting that weight gain and loss are far more complicated than simply a matter of counting calories or energy ingested, or taking a 'fat pill' to lose weight. The best approach, as always, is the holistic one: to treat the body as a single interrelated whole, and to provide it with the best fuel, the best workout and the best rest (see box, page 13). Under these conditions, weight normalizes naturally.
Factfile: In search of the artificial fat regulator
After leptin was discovered in 1994, the medical industry and academic centres were convinced that they had found a solution to obesity: simply administer extra leptin to the obese. Nevertheless, these hopes were soon dashed after it was discovered that the overweight tend to suffer from leptin resistance. Those who took hormones lost weight only temporarily and soon yo-yoed back to their normal state of overweight, as the brain became accustomed to the extra levels of hormone and again ignored it.
Currently, researchers are working on a method of chemically overcoming leptin resistance. Scientists at Harvard Medical School have shown that two agents-buphenyl or 4-phenyl butyric acid (4-PBA) and taurousodeoxycholic acid (TUDCA)-can prevent the brain from ignoring leptin. Both are ordinarily given as treatments for cystic fibrosis and liver disease.
In the study, when Dr Umut Ozcan and his team gave mice 4-PBA or TUDCA, leptin sensitivity was boosted 10-fold, and the mice lost significant weight even when eating a high-fat diet (Cell Metabolism, 2009; 9: 35-51).
As Ozcan noted, this study was the first to show that leptin could be turned on in mice, despite being fed a high-fat diet.
The 4-PBA and TUDCA molecules are considered 'chemical chaperones', which help to increase the capacity of the cells' endoplasmic reticulum (ER) to fold proteins. However, in addition to the fact that this research is only in animals and, so, may not apply to humans, the real problem is that we don't yet understand the precise mechanism behind ER stress in overweight people who consume a high-fat diet.
At this time, Ozcan's team is still attempting to understand leptin sensitivity more precisely in order to develop drugs that can turn on brain signalling more efficiently than can these two drugs.
Meanwhile, research scientists at the Scripps Research Institute in La Jolla, CA, have developed an anti-obesity vaccine, which targets ghrelin by making use of immune-system antibodies to bind to selected targets, thus stimulating an immune response against them. In theory at least, this is supposed to prevent ghrelin from reaching the central nervous system, thereby tricking the brain (and so the body) into feeling 'full'. So far, the vaccine has been successfully tested in rats, but not in humans (Proc Natl Acad Sci U S A, 2006, 103: 13226-31).
Using another prong of attack, San Diego-based Amylin Pharmaceuticals is carrying out clinical trials of leptin supplementation with a drug to increase leptin sensitivity.
Nevertheless, Tamas Horvath, a neuroscientist at Yale University, believes this kind of artificial engineering could be a recipe for disaster, as it might simply encourage the cells to keep on growing. It's also not necessary, he says, considering that there are many other proven ways to restore leptin function (see box, page 14).
Factfile: Burn fat in your sleep
As a society, we're not only fatter than ever-the incidence of obesity has doubled in the US from 1960 to 2002, and increased fourfold in the UK from 1980 to 2002-but we're also getting a good deal less sleep. Indeed, the percentage of young adults who get 8-8.9 hours of sleep per night has
been cut nearly in half-from 40.9 per cent in 1960 to 23.5 per cent in 2002 in the US.
Furthermore, other evidence has shown that not getting enough sleep affects blood levels of both leptin and ghrelin, as well as hunger and appetite levels (Ann Intern Med, 2004; 141: 846-50).
These two pairs of factors are now thought to be related, according to recent Canadian research. A six-year study from Quebec of 323 men and 417 women, aged 21 to 64 years, showed that the less sleep obtained every night, the higher the fat indices and the lower the levels of leptin. Those who reported getting seven to eight hours of sleep had significantly higher levels of leptin and lower fat indices than those who'd only managed to get five to six hours of sleep every night.
The researchers concluded that short sleep durations result in an increased risk of an individual being overweight because of lower leptin levels than would be predicted by fat mass alone. Also, there may even be an optimal number of sleeping hours at which body weight is regulated and maintained (Obesity [Silver Spring], 2007; 15: 253-61). This suggests that getting an optimal amount of sleep (seven to eight hours-no more, no less) does more than keep you alert; it also helps you to regulate your weight.
Factfile: Powering up the Fat Burners
Although leptin supplements have been shown not to work, you can regulate your fat-burning hormones by following a number of important lifestyle choices.
u Eat a highly varied, fresh, organic diet, with the bulk composed of highly nutritious, colourful fruits and vegetables, and herbs
u Strive to eat nine or 10 fruits and vegetables every day, rather than just the recommended five, says Dr Leo Galland, author of The Fat Resistance Diet (Broadway Books, 2005)
u Vegetable choices that help fat regulators include cruciferous vegetables such as broccoli and cabbage, carrots, leeks, onions, spring onions, garlic, asparagus, bell peppers, arugula and romaine lettuce, spinach and tomatoes
u The best fruits for stoking fat-burning hormones include bananas, apples, blueberries, cherries, oranges, grapefruit
u Some of the best herbs for fat-burning include ginger, ginseng, cinnamon, bilberry, chamomile, chasteberry,
green tea, peppermint oil, turmeric, dandelion, aloe vera
u Use spices liberally in your food
u Pepper your diet with fresh, uncooked and unsalted nuts, such as walnuts, linseeds (flaxseeds), sesame seeds and almonds
u Ensure that you have an adequate intake of omega-3 essential fatty acids, the best animal sources of which include cold-water fatty fish such as salmon and tuna, but which are also found in plant sources such as walnuts, linseed and pulses (such as soy, kidney and navy beans)
u Take regular sweat-producing exercise, as regular aerobic exercise helps to increase leptin production, although following the right diet will cause leptin levels to regularize naturally
u Look to grains with a lower glycaemic index (GI), such as pasta, brown rice, quinoa, millet, oats and barley
u Cut out or cut down on refined sugar-in all its forms
u Watch your carbohydrate intake, and stay off the white
stuff by avoiding all processed foods, such as white bread, potatoes, white rice, pastries, cakes and the like, and
high GI foods such as beer
u Take high-quality supplements that are rich in B vitamins, particularly B12, plus omega-3 fatty acids, magnesium, zinc and coenzyme Q10, which counteracts inflammation
u Avoid fake low-calorie foods, especially artificial sweeteners and diet soft drinks, now found to slow weight loss (JAMA, 2009, 302: 2477-8)
u Eat three good meals a day and don't snack
u Don't eat late at night
u Include protein in your breakfast meal
u Get 7 to 8 hours of sleep a night-no more, no less
u Drink plenty of water, green and black teas, and blueberry, cherry, pomegranate and vegetable juices.
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