The perfect diet pill has eluded the drug industry for decades,
but now molecular genetics has put the field on the map and offered new ways
to fight the "battle of the bulge".
In the past few decades, technological innovations have created a society
where most forms of work are lighter, travel less strenuous, and lifestyles
more sedentary. Add to this the overconsumption of food, in particular high-fat
convenience foods, and you have the perfect recipe for a ballooning public
health problem—obesity. With little insight into how body weight is
controlled, to date most treatments for the dangerously overweight has been
at best ineffective, but harmless, and at worst dangerous or invasive (e.g.,
surgical reductions in stomach volume). In recent years, however, genetics
and molecular biology have helped elucidate some of the intricacies of the
body's weight control system, serving up some potentially safe and effective
therapeutic strategies.
A growing problem Obesity is not just a cosmetic issue, but a serious medical problem, the
prevalence of which is steadily increasing. The World Health Organization
(Geneva) and its International Obesity Task Force recently declared that obesity
is a global epidemic that "pose[s] one of the greatest threats to human
health and well being". Public health experts have estimated that more
than half of all Americans over the age of 20 years are overweight, and that
at least 20% of males and 25% of females are clinically obese. The last comprehensive
study carried out in the United Kingdom suggested 17% of men and 20% of women
in England and Wales were obese, and studies in the late 1980s suggested that
at least half of Europe's adult population was overweight (see "Whom are we calling fat?").
The United States may be the leader in the obesity stakes, but other nations
are catching up. Diverse reports show that the prevalence of the condition
is increasing throughout the developed world, and obesity has become common
in Southeast Asia, Latin America, and the Middle East (see
Table 1).
Table 1. The expanding world: the prevalence of obesity (BMI>30) globally
Obesity has been recognized as a significant risk to health since 1959,
when the Metropolitan Life Insurance Company published a set of actuarial
tables showing a strong correlation between excess body weight (and thus Body
Mass Index, BMI) and the risk of premature death. In what has become a classic
study of the link between weight and mortality, 115,000 women enrolled in
the Nurses' Health Study provided detailed information of the association
of BMI with premature death and specific diseases. The risk of premature death
increased with body weight over the healthy norm, and the risk doubled when
the BMI exceeded 29. Data from other studies show similar results among men.
Overweight or obesity also greatly increases the risk of hypertension, type
2 diabetes, cardiovascular disease, respiratory problems, and a number of
cancers. The increased burden is also an economic drain on a nation. The Institute
of Medicine estimates that the direct health care costs and loss of productivity
resulting from ill health costs the United States more than $70 billion a
year.
There is little doubt that the cause of obesity is both social and behavioral.
"Twin and family studies indicate that genetic factors play a role in
most individuals who are obese," says Gregory Barsh, an obesity researcher
at Stanford University (Stanford, CA), but genetics is not the major factor
driving the current epidemic. "A combination of extrinsic conditions
are able to cause obesity in individuals who are . . . genetically predisposed,"
says Barsh.
The dieter's dilemma The cause of obesity is ultimately a question of simple thermodynamics:
if calorific intake exceeds the output then the surplus accumulates as fat.
In theory, drugs could work through any of four mechanisms (see
Figure 1): reducing the amount of fat absorbed, increasing fat metabolism,
curbing appetite, or resetting the central controls of body weight.
Figure 1. The key elements of the body's weight-control system, highlighting
the potential routes for therapeutic intervention.
Central to weight homeostasis is leptin, which balances anabolic (resulting
in weight loss) and catabolic (resulting in weight gain) effectors through
the hypothalamus. * indicates compounds already approved by
the Food and Drug Administration.
In the first category is Xenical (orlistat), Roche's (Basel, Switzerland)
drug that blocks the breakdown and absorption of about 30% of dietary fats.
However, the side effects, which include fatty stools and fecal urgency, have
deterred many patients. An alternative strategy is to permit fat digestion
to take place in the gut, but then block the uptake of fatty acids. The discovery
of a fatty acid transporter (FATP4) may provide a target for the development
of small-molecule therapeutics that work in this manner.
Enhancing energy expenditure, primarily by stimulating thermogenesis (heat
production), is a second strategy. Thyroid hormones, for example, "burn
off" fats, although they cause detrimental side effects like loss of
bone calcium.
Alternative targets include uncoupling proteins (UCPs), which were first
discovered in brown fat and also metabolize fats, creating heat. Increasing
the expression of UCPs could be one approach to treating obesity. Agonists
of the 3-adrenergic receptor are also under investigation
as targets for increasing energy expenditure and Sanofi-Synthelabo (Le Plessis,
France) has one such product in development (see Table 2).
Table 2. Selected obesity treatments in development
An alternative means of controlling consumption is by harnessing peripheral
control of feeding. Peptides produced by the gastrointestinal system and pancreas
naturally regulate feelings of satiety ("fullness') and the amount of
food consumed. One of the best understood is cholecystokinin (CCK), and others
include neuromedin B, gastrin-releasing peptide, and enterostatin. Such peptides
could be used as targets for drugs that could modulate the amount of food
consumed during a meal, but would likely not be effective at longer term control
of body weight.
To date, centrally acting appetite suppressants have proved the most commercially
viable (see Table 2). However, the fate of two highly
publicized weight-reducing drugs has cast a long shadow over the field. The
highly publicized withdrawal of Redux (dexfenfluramine) and fenfluramine,
which were used in combination with phentermine in the fen-phen diet drug
(see "Heartache for AHP"), has left the public
with lingering doubts about new obesity therapies. Indeed, Xenical has struggled
to become the blockbuster drug it was touted to become. However, a new sense
of optimism has been created within the industry following genetic studies
first focused on a grossly overweight mouse.
Million-dollar mice In 1994, great excitement was generated when researchers at the Howard
Hughes Medical Institute at the Rockefeller University (New York, NY) discovered
what appeared to be a fat-regulating hormone, leptin.
Jeffrey Friedman and his team had identified and sequenced the ob
gene, which underlies the gross obesity in the ob/ob strain of mice1. When leptin was injected back into the ob/ob mice their
appetites shrank and they quickly shed the excess weight. Researchers were
most excited to see that fat was lost and lean mass spared—the ideal
diet drug.
Amgen (Thousand Oaks, CA) moved quickly to pay $25 million for the rights
to develop leptin as a treatment for obesity. Clinical results, however, have
been disappointing. "There were some reasons to wonder how well it would
work, given the presence of high levels of endogenous leptin in [obese] people,"
explains Jeff Flier, an obesity researcher at Harvard's Beth Israel Deaconess
Hospital (Boston, MA). It seemed unlikely that further elevations would restore
the patients' sensitivity to leptin. Indeed, Amgen ended clinical trials of
leptin in 1999 after a series of unimpressive results. The company is now
testing a new formulation of the protein, which may be more stable, and last
longer, in the bloodstream.
"I don't like to say it's over for leptin," says Louis Tartaglia,
vice president for metabolic diseases at Millennium Pharmaceuticals. The hormone,
he says, could still be used to treat a subset of obese patients. For example,
leptin has been used successfully to treat a handful of severely obese children
who have an inherited deficiency in the hormone.
Lessons from leptin However, the discovery of leptin marked the beginning of molecular medicine
for the treatment of obesity, giving the field a credibility hitherto lacking.
Leptin's discovery touched off some fundamental research into the mechanisms
controlling body weight, producing a trove of new molecular targets for obesity
therapies.
Shortly after the discovery of leptin, Tartaglia and his colleagues identified
a receptor for leptin, OBR. A truncated form of the receptor, so-called OBR-A,
shuttles leptin across the blood−brain barrier. Researchers now suspect
that obese people appear to be resistant to leptin because the hormone is
not transported into the brain. Indeed, studies suggest that the level of
leptin in the cerebrospinal fluid of obese individuals is much lower than
anticipated considering their high blood concentrations. OBR-A is therefore
an as yet unexplored target for treatment.
Leptin is produced by fat cells, circulating in the blood to the hypothalamus
where it works through a number of nuclei and pathways to reset the body's
weight controller. As fat levels increase, leptin levels rise, triggering
a reduction of food intake and increasing metabolism. As shown in
Figure 1, leptin mediates its effects through at least two subtypes
of neurons of the arcuate nucleus of the hypothalamus, those expressing neuropeptide
Y and those expressing pro-opiomelanocortin (POMC).
Sites for intervention Leptin inhibits the release of neuropeptide Y (NPY), a small protein that
increases appetite. Research efforts have now focused on developing NPY antagonists,
and companies such as Neurogen (Bradford, CT) and Synaptic Pharmaceuticals
(Paramus, NJ) are targeting specific subtypes of receptor, NPY1 and NPY5,
which have been implicated in feeding.
Another element in the leptin signaling pathway is -melanocyte-stimulating
hormone (-MSH), which is actually a fragment of the precursor protein
POMC. Mutations in the POMC gene cause a rare hereditary form of obesity. -MSH
acts through the MCR-4 receptor to reduce appetite. According to Barsh's data,
mutations in MCR-4 account for 2−3% of cases of severe obesity, and
agonists of the MCR-4 receptor make obvious choices for the development of
a treatment for obesity and one that Millennium is currently pursuing.
In addition to its effects on -MSH, leptin increases the production
of the SOCS-3 (suppressor of cytokine signaling-3) protein, which terminates
its activity at the leptin receptor. The SOCS-3 protein is probably a regulator
of the leptin signaling pathways in healthy individuals. If this pathway is
overactive in obese patients, drugs that target SOCS-3 might have considerable
potential.
Finally, a new target appeared in June 2000, when researchers at Johns
Hopkins University (Baltimore, MD) discovered that the molecule malonyl coenzyme
A inhibits NPY independently of leptin, decreasing appetite in mice2.
The team also developed an inhibitor that prevents malonyl CoA from being
broken down in the body, resulting in its accumulation and leading to weight
loss.
Although a number of other neuropeptides are known to be involved in the
central control of appetite, many of these are not suitable targets for drug
development because they play roles in a wider range of physiological processes.
Further research into neuropeptides such as corticotropin-releasing hormone
(CRH), orexin, galanin, and cocaine- and amphetamine-regulated transcript
(CART) may, however, help clarify the workings of the weight control system.
Drugs targeting any of these pathways would act primarily as appetite suppressants,
and strike at the heart of the dieter's problem. Drugs that reduce fat absorption
or increase fat metabolism may help shift body fat, but in turn they will
modulate leptin levels triggering the compensatory changes in feeding and
metabolism. Ultimately, appetite suppressants, which work by resetting the
body's weight control system, is what drug developers are placing their bets
on.
However, even then Tartaglia argues that therapies may have to be tailored
to specific subpopulations of patients. "Right now it's very difficult
to predict which of these different mechanisms is going to really result in
the most effective obesity drugs, and in fact I think it's very likely that
different drugs acting on different mechanisms will be more or less effective
in different people."
Fat chance A deeper understanding of the molecular mechanisms underlying weight control
has helped to inform many drug development efforts, but serendipity has also
played a role. Regeneron (Tarrytown, NY) initially tested Axokine (ciliary
neurotrophic factor, CNTF) as a treatment for amyotrophic lateral sclerosis
(ALS or Lou Gehrig's disease). Although Axokine did not alleviate ALS, it
caused the patients to lose weight. Subsequent studies revealed that Axokine
"used the same signaling pathway [as leptin], and it was doing it in
an overlapping part of the brain. . .," says George Yancopoulos, chief
scientific officer at Regeneron.
So far, CNTF has fared better than leptin in clinical trials. In a phase
2 trial involving 170 obese people, patients given the drug lost 3 to 9 lb
over a 12-week period. One group of patients was followed for a few weeks
after they stopped taking the drug, and Yancopoulos says that they didn't
regain their body weight. "They actually stayed at that plateau of the
body weight that they had lost." This finding raises the possibility
that the drug could reset the body weight for the longer term.
Others are less optimistic that weight loss can be maintained without chronic
and long-term treatment. "It's very . . . unreasonable to expect that
you are ever going to be able to take a [weight loss] drug for a short period
of time and then be able to stop taking it and stay thin. Short of something
radical like gene therapy, I think that would be an unrealistic expectation
at this point," says Tartaglia.
A difficult delivery The prospect of long-term administration raises another problem with many
of the potential biotechnology-based obesity treatments: as proteins, they
will need to be injected, and many have short half-lives. Regeneron is currently
working with Emisphere (Tarrytown, NY) to develop oral formulations of CNTF,
but Yancopoulos says that those are hurdles that will have to be crossed in
the future. However, he is optimistic about the prospects for injected treatments:
"I think that the barrier for an injection is much lower . . . than
people would have you think. These are very small amounts of drug that we
need to inject, so I think for severe obesity an injectable is not going to
be much of a problem."
Tartaglia takes a similar tack: "It's certainly a challenge to get
proteins that have very long durations of action, but that's also a challenge
for orally administered small molecules. I don't really see it as a special
issue unique to proteins [as obesity treatments]." The advantages and
disadvantages of the two approaches should become clear as the large number
of small-molecule and protein-based therapeutics move through clinical development
(see Table 2),
Indeed, most researchers are optimistic about the prospects for new obesity
therapies. "I expect new pharmacological treatments will be implemented
over the next 5−15 years. It would not be surprising to see new drugs
available in the next 2−3 years, but it will take another 2−3
years to measure their effectiveness," says Barsh.
A healthy diet and regular exercise are still the best ways to prevent
obesity, but something more will be needed to combat the current obesity epidemic.
According to Flier, "The old 'diet and exercise' approach has clearly
not worked very well, so there's plenty of room for improvement."
3-adrenergic receptor are also under investigation
as targets for increasing energy expenditure and Sanofi-Synthelabo (Le Plessis,
France) has one such product in development (see 
-melanocyte-stimulating
hormone (
