Courtesy of Ray Clark & Mervyn Goff/Photo Researchers, Inc.
"I'm a potential obese person," says Steve Bloom of Imperial College London. "I feel hungry all the time and have to keep [jogging] and restraining myself when they put chocolate biscuits on the table.... I keep my weight down, but I've still got a potbelly. And that's in spite of being an [obesity] expert and knowing what I'm supposed to do."
Which, presumably, is to burn off and eliminate as many calories as one eats. It's an equation that is getting increasingly out of kilter, and a problem that science has been trying to tackle.
A recent review describes the past 10 years as the "golden age" of obesity research.1 In that time, researchers have worked on a smorgasbord of molecules involved in body weight regulation via many overlapping systems and pathways. They have identified genes, including melanocortin 4 receptor and prohormone convertase 1, in which mutations lead to morbid obesity through their effects on appetite and metabolism.
Investigators also are pinning down the roles of leptin, ghrelin, protein YY (PYY), and cholecystokinin. These hormones are produced by fat cells and the digestive tract and act on long- and short-term energy balance via the central nervous system. Hopes are high that obesity will soon be controlled in a chemical fashion. Big favorites include drugs that block receptors for the cannabinoids, long known to stimulate hunger. Some researchers even have slim hopes for angiogenesis inhibitors, which are more associated with cancer therapies.
"We've come from a situation essentially, in 1994, where we had no molecular targets, to one where we have a profusion," says Cambridge University geneticist Steve O'Rahilly. The situation can appear chaotic, says Matthias Tschöp of the University of Cincinnati's Obesity Research Center. "Sometimes, you think nobody's ever going to understand this; everything's linked to everything else."
It won't be easy, agrees David Cummings of the University of Washington, Seattle. "The task for ensuing years is to sort through them one at a time and find out which are the key players and which are the ancillary ones."
It's a task whose successful outcome could benefit many. The World Health Organization estimates that over one billion adults worldwide are overweight, defined as a body mass index (BMI, in kg/m2, calculated as body weight divided by height squared) greater than 25; 300 million are considered obese, with a BMI greater than 30. It is widely hailed as an epidemic, and just in case that doesn't sound serious enough, WHO has coined a new word, globesity, to describe the situation. In the United States, 31% of adults are obese, compared to 23% a decade ago.2 The rest of the western world isn't far behind, and developing nations are starting on a similar trajectory.
As the numbers of the obese have increased, so too have associated disorders such as cardiovascular disease, type 2 diabetes, stroke, and certain cancers. Edinburgh University endocrinologist Jonathan Seckl says that the number of new referrals to his diabetes clinics has gone up threefold in the last decade. "That's not because we're finding more cases, it's because there
PUTTING THE BRAKES ON:
The body produces hormones that act through the brain to regulate short- and long-term appetite and also the body's metabolism. The sources of several of the hormones now being studied are shown. (Reprinted from
Obesity is also about money. Last year, the United States spent $75 billion on medical expenditures attributable to obesity; about one-half of this money came from public coffers.3 The US Federal Trade Commission estimates that North Americans spend $35 billion per year on weight-loss products and programs. "Industry has recognized that this is the largest possible market worldwide ever," says Tschöp. "This is a large amount of people that will have to take a drug until the end of their life, and those people have money." Seckl, whose team identified 11beta-hydroxysteroid dehydrogenase, an enzyme linked to obesity, says that one drug company recently sold an inhibitor for $86 million.
PAST AND PRESENT
There is no question that profound genetic influences affect weight regulation. Humans who lack leptin, an appetite-suppressing hormone produced by fat cells, or melanocortin-4 receptor, which is downstream of leptin in the hypothalamus, have insatiable appetites. "Their phenotype is dominated by their hyperphagia," says O'Rahilly. "I mean these kids just eat like crazy."
While such debilitating mutations are very rare, more subtle predispositions to plumpness are not. The problem is that we owe our genetic make-up to the selection pressures exerted by a once kill-or-be-killed environment, very different from the one that operates now. Humans are designed to put on weight rather than lose it, and the thrifty nature of our genes encourages us to take full advantage of modern life's tasty trappings. It's "an obesogenic environment," says Bloom. "I think it's a tribute to our self-control that we're only this obese."
This evolutionary necessity of maintaining body weight also might shed some light on the apparent complexity of the regulatory system. "It is very important to eat to survive," says O'Rahilly, "so it's likely that we'll have put in multiple fail-safe mechanisms to try and ensure that we do continue to eat." In other words, the pathways involved in appetite regulation watch out for each other; if one is cut off, another takes over.
Tschöp cites the gut hormone cholecystokinin as an example of appetite regulation. It can be given to induce satiety in the short term, but in the long-run, caloric intake returns to where it was. Tschöp says that other specific examples of such physiological redundancy have proved elusive. "Everybody is talking about redundancy," he says, "but where are the actual data?"
Trying to integrate the plethora of weight regulatory pathways is "still premature," says Seckl, "but you can begin to come up with some principles." Indeed, one pathway has emerged as being of central importance.
FAT OF THE GLAND
©2004 Elsevier Science
Leptin acts directly on arcuate nucleus neurons coexpressing NPY and AgRP, and POMC and CART, via the ObRb form of the leptin receptor expressed on these cells. The former neurons stimulate anabolic and orexigenic effects and are suppressed by leptin; the latter neurons stimulate catabolic and anorexic actions, promoting weight loss. Downstream, these neurons target neurons expressing melanocortin 4 receptors that are activated by the POMC product α MSH, and inhibited by the neuropeptide AgRP. Activation of these neurons promotes catabolism by reducing food intake and increasing energy expenditure. (Reprinted from
Leptin, an appetite-suppressing hormone secreted by fat cells, is "a truly critical player in the field," says Cummings. Its discovery in 19944 is widely credited with starting this golden age of research. "If you asked people about adipose tissue 10 years ago, everyone said, well, it's a tedious insulator and store for fat. And that was the sum of world knowledge," says Seckl. "Now we have a dozen new hormones which come out of it."
Leptin receptors were soon identified in two populations of neurons in the arcuate nucleus of the hypothalamus. One population produces the appetite-stimulating neuropeptides NPY (neuropeptide Y) and AgRP (agouti-related protein), which are suppressed by leptin, while POMC (proopiomelanocortin) and CART (cocaine- and amphetamine-related transcript) neurons suppress appetite and are activated by leptin. As fat stores are reduced, so is the amount of circulating leptin, causing appetite to increase.
Should We Shoot the Messenger?
Cambridge geneticist Steve O'Rahilly cites that old chestnut of freewill versus determinism as an example of how obesity interacts potently with social and philosophical issues. "If you're slim, you like to think there's a lot of control involved. If you're fat, you like to think it's out of your hands."
There are people in the United Kingdom who think the obese could use help in the control area: A rising tide of opinion suggests that the advertising of sweet and fatty foods, particularly to children, makes a significant contribution to the growing incidence of obesity.
The FSA's recommendations follow the publication of a report suggesting that television advertising affects children's food preferences and behavior.3 But David Ashton, a clinical epidemiologist at Imperial College London, argues that the report fails to identify the magnitude of the effect and, therefore, whether regulation would have any useful impact on obesity.4
Ashton points to Quebec, where obesity rates are no different from other Canadian provinces, despite a 1980 ban on advertising food to children. A similar, decade-long ban in Sweden also has been ineffective, he says.
Peter Marsh, a director at the Social Issues Research Centre, also is skeptical. "Obesity is most related to processes like urbanization and social change rather than to single factors," he says. "Some of the highest obesity rates are in places like Morocco and Uzbekistan. [These are] not countries where McDonald's has a particularly significant presence."
The FSA's Jonathan Back accepts that a causal link between advertising and obesity remains to be shown. "It would be nice to have definitive evidence, but sometimes you've got to go with what you've got," he says. "We don't want to turn into the food police, but we've got to think of the future of our kids."
Ashton believes the current focus on food advertising detracts attention away from more challenging problems, such as the lack of opportunity for physical exercise in schools. Marsh agrees. "It's not by and large white middle class kids who are becoming obese, it's kids from poorer families," which, he says, ties in with education, aspiration, and various other factors. "I fear that most government approaches take the most financially advantageous line," says Marsh. "The trouble is, they don't work."
- Stuart Blackman
Hopes that leptin could be used to suppress appetite pharmacologically were dashed, however, when it was found that most obese people have high levels of the hormone; they are resistant, rather than deficient. The mechanism for leptin resistance remains unresolved, but a new study from William Banks at the Veteran Affairs Medical Center, St. Louis shows that triglyceride fats, which are elevated in obesity, impede the transport of leptin across the blood-brain barrier, preventing it from reaching its receptors in the hypothalamus.56 All the known monogenic mutations (leptin, leptin receptor, POMC, prohormone convertase 1, melanocortin 4 receptor) that lead to hyperphagia in humans are in the leptin-hypothalamic system (see diagram at left).
The melanocortin 4 receptor is a particularly hot target because it is locally expressed in the brain. Cummings explains that current anti-obesity drugs are relatively nonspecific. Sibutramine (Meridia), for example, tinkers with serotonin levels. "Manipulating them is fraught with side effects," he says, "and those limit the doses you can use."
The identification of another system involving the hypothalamus has led to the development of one of only two potential anti-obesity drugs currently in Phase III clinical trails. The positive effects of marijuana on appetite have long been known, and in the 1990s, a receptor for endogenous cannabinoids was identified in the hypothalamus. Sanofi-Synthelabo has developed a blocker for the cannabinoid receptor CB1, called Rimonabant, and trials have revealed spectacular effects on reducing body weight, waist size, and normalizing lipid metabolism.7
O'Rahilly points out, however, that more people withdrew from treatment than from placebo groups, so "there were clearly some side effects." An obvious concern might be that blocking a receptor linked to a mood-altering drug might have negative psychological consequences. Yet Marie-Camille Borde, who heads Sanofi-Synthelabo's Rimonabant research group, says that depression indices reveal no difference between treatment and placebo groups.
BLOOD AND GUTS
Although the current emphasis is on appetite regulation, it is theoretically possible to target the energy equation's other side, by manipulating energy expenditure. Drugs that raise metabolism, such as beta 3 agonists and modified forms of thyroxin, have been tried before but were only marginally effective and/or toxic. Dinitrophenol, for example, worked by disrupting oxidative phosphorylation in mitochondria. "Very effective," says O'Rahilly, "but it killed people."
Less distinction exists between metabolic and appetite targets than was once thought, says O'Rahilly. Many hypothalamic targets, he says, seem to affect both. Indeed, "It's hard to find one that doesn't." Low levels of leptin induce other physiologic systems such as reproductive and immune functions to conserve calories when energy reserves are low.
Another approach might be to prevent fat formation in the first place. Angiogenesis inhibitors prevent blood vessel formation; they have been developed with a view to treating cancer by starving tumors. But as adipose volume increases, new blood vessels are required to supply it. Maria Rupnick of Boston's Brigham and Women's Hospital has shown that not only can leptin-deficient
There are concerns, however, about the long-term effects of preventing fat formation. "If you do not have adipose tissue in which to put those extra calories, where are you going to put them?" asks O'Rahilly. "You are probably going to put them where they shouldn't be, in the liver, muscle, pancreatic beta cell. And we know that's very bad." Rupnick points out that no adverse health consequences have been seen so far in experimental animals, and she suggests that the excess calories might be accounted for by an increase in metabolic rate.
While the leptin system is regarded as a long-term regulator of energy balance, other pathways are under scrutiny for their effects on short-term, meal-to-meal appetite regulation. The intestine produces PYY after a meal, inhibiting NPY in the arcuate nucleus. It is a particularly attractive target because it appears to have a causal role in obesity. Bloom's group has found that it reduces appetite in mice9 and humans.10 Furthermore, PYY is underexpressed in obese patients, and this can be corrected, in the short-term at least, by treatment with PYY. "A peripheral injection of gut hormone produces a blood level rise and acts exactly as if you'd eaten a meal," says Bloom, "So it's not going to be at a risk of massive side effects, because that's what happens every time you eat a meal." However, some controversy surrounds the rodent work owing to a "widespread inability of people to replicate the results," says Cummings. Bloom says that he is about to start longer-term trials on human subjects.
Further up the digestive tract, ghrelin, secreted in the stomach, has been dubbed the hunger hormone for its stimulatory effect on appetite. Cummings' group has shown that in humans, circulating ghrelin levels rise before meals and fall rapidly after eating.11 Ghrelin also increases after dieting, suggesting that it is one way the body fights against weight loss.
"In the beginning, we thought, well, it's a hunger hormone from the stomach, [so] it does something in the brain. Let's block it and we have an obesity drug," says Tschöp, who was part of the Eli Lilly group that first identified the peptide's appetite-stimulating effects. But, just as leptin levels are high in obesity, ghrelin levels turned out to be low. Furthermore, ghrelin knockout animals are of normal weight. Blocking the remaining ghrelin in obese patients might still prove to help weight loss, but progress is hampered by the lack of suitable ghrelin receptor antagonists.
Meanwhile, leptin continues to surprise. Two recent papers show that the hormone can rewire neuronal circuitry in the hypothalamus.1213 "You know those old movies where somebody at a telephone exchange center connects people by unplugging and plugging cables? That's pretty much how that works," explains Tschöp.
Leptin exposure suppresses excitatory inputs to NPY neurons and promotes them in POMC neurons. Ghrelin also alters these inputs, but in a direction opposite to leptin. Disruptions to the wiring in
Until then, there's always surgery. Gastric bypass might seem a drastic solution to the battle of the bulge, but it is effective: Weight comes off, and it usually stays off. Appetite is suppressed, which is likely linked to observations that postoperative levels of PYY and ghrelin are high and low, respectively.
THE ENERGY BALANCE SYSTEM
©2004 Elsevier Science
involves long-term afferent signals from fat (leptin) and pancreatic β cells (insulin) and short-term, meal-related afferent signals from the gut, including inhibitors of feeding (PYY, GLP-1, and CCK) and the stimulator of feeding (ghrelin). Efferent outputs regulate appetite, energy expenditure, hormonal milieu, energy partitioning, and the status of reproduction and growth. (Reprinted from
It's an expensive procedure, although Cummings says it pays for itself in the long run because it removes the need to take many of the costly medicines that obese people require. For example, many obese people have diabetes, and 83% of those are cured wholesale, often while still in the recovery room, says Cummings. "It's a kind of a mystical thing."
Cummings predicts that surgery will be outmoded as more effective medicines are developed. He suggests that in the same way that hypertension is treated with multiple classes of drugs working on many different sites, the same will evolve for excess body weight over the course of the next couple of decades.
Tschöp prefers a parallel with interventions in reproductive physiology. He points to the use of progesterone to trick the brain into believing that a woman is pregnant. "I'm sure that ... we'll be able to target the exact, essential mechanisms and trick the brain into believing the stomach is already full." He adds, "Maybe we don't yet know the progesterone of energy balance."