7 FEBRUARY 2003 VOL 299 SCIENCE www.sciencemag.org846

When Mae West said that too much of agood thing can be wonderful, she wasnttalking about food. Over the past 50 yearsor so, food availability has soared, at leastin the developed world, and too much foodhas turned out to be far from a good thing.That order of fries you buy in your localfast-food restaurant isnt the only thingthats become supersized in the UnitedStates: So has the national waistline.

By current estimates, 30% of U.S. adultsare obeseroughly double the percentage20 years agoand another 35% are over-weight. Children and adolescents haventbeen immune to this obesity epidemic; 15%are too fat. All this excess poundage is muchmore than an aesthetic issue; obesity is a ma-jor risk factor for such life-threatening dis-eases as type II diabetes (Science, 26 April2002, p. 686), heart attack, stroke, and sometypes of cancer, including breast and coloncancers. Indeed, some 300,000 people die ofobesity-related diseases every year in theUnited States alone.

But theres a glimmer of hope. Re-searchers have learned a great deal abouthow the body regulates its weight. Weknow that there are physiological systemsin place that seem to be involved in main-taining weight, says obesity researcherJeffrey Flier of Beth Israel DeaconessMedical Center in Boston.

One of these systems is primarily con-cerned with short-term weight regulationhow often and how much we eat on a givendayand the other with longer-term regula-tion. Over the past few years, scientists haveidentified numerous components of each.Recently, for example, two peptide hor-mones produced by the digestive tract,known as ghrelin and PYY, have beenlinked to short-term feeding behaviors,whereas leptin, and to a lesser extent, in-sulin, are key to weight maintenance overmonths and years.

Obesity researchers have also madeprogress toward understanding how thesehormones exert their effects. Among otherthings, theyve found that certain brain re-gions, such as the arcuate nucleus, play acritical role in integrating the hormones ac-tivities, sending signals that tell the body toadjust its food intake and energy expendi-ture. A coherent wiring diagram can now bedrawn showing how these hormones work,says leptin discoverer Jeffrey Friedman of

Rockefeller University in New York City.The pharmaceutical industry has been

having great difficulty coming up with anti-obesity drugs that are both safe and effective(see p. 849), but the wealth of informationnow being gained should provide severalnew drug targets.

In one regard, though, the message com-ing out of this work is depressing for peoplewho want to lose weight: The bodys weight-control systems have apparently been de-signed to protect more against weight lossthan weight gain (see Friedman Viewpoint onp. 856). That undoubtedly reflects humanevolutionary history in which, until very re-cently, food scarcity, not overabundance, wasthe danger. As geneticist Rudolph Leibel ofColumbia University College of Physiciansand Surgeons in New York City says, youcan bemoan the fact that were set up thisway, but its whats gotten us here.

Long-term savingsThe discovery that helped kick off thecurrent surge of obesity research wasthe Friedman teams identificationof leptin in 1994. Interest in thearea exploded as a result, saysgeneticist Stephen ORahilly ofthe University of Cambridge,U.K.: It was the first [anti-obesity] hormone youcould get your hands on.

Friedman and his col-leagues found leptin bytracing the gene at fault ina mutant strain of extreme-ly obese mice and went onto show that they couldcure the animals obesity by treating themwith the hormone. It produced weight lossby decreasing the animals appetite whileat the same time revving up their metabol-ic rates. As humans have their own versionof the leptin gene, the results grabbedeveryones attention. Would leptin prove tobe the magic bullet that would cure theever-growing human obesity problem?

Those hopes were soon dashed. Somerare cases of human obesity are caused bydefects in leptin production. ORahilly,Sadaf Farooqi, also at Cambridge, andtheir colleagues have recently used leptinto treat three children who were extreme-ly obese because they dont make thehormone. The childrens weights quickly

dropped, mainly because they ate much lessthan before, the researchers reported in theOctober 2002 Journal of Clinical Investiga-tion. Although leptin deficiencies are rare,they are treatable, ORahilly says.

But unlike such patients and the mutantmice, most obese humans turned out to havehigher than normal blood levels of leptin,which is produced by fat cells. For reasonsnot yet understood, they are resistant to itsactions. Thats one reason why many obesityresearchers now think that leptins main roleis protecting against weight loss in times ofdeprivation rather than against weight gain in

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Cellular Warriors at the Battle of the BulgeResearchers are picking apart the molecular signals the body uses to regulateits weightwork that may lead to new antiobesity drugs

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Appetite controllers. The body produces hormonesthat act through the brain to regulate short- and long-term appetite and also the bodys metabolism. The diagram shows the sources of several of the hormonesnow under intensive investigation.

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times of plenty.When a persons fat stores shrink, so

does leptin production. In response, appetiteincreases while metabolism decreases.But the converse does not happen. Beyonda certain point, increased leptin productiondoes little to inhibit appetite or increasemetabolism. The

system is designed to defend itself againststarving to death and not being able to re-produce, Leibel says.

Although leptin is not very effective fortreating garden varieties of human obesity,its discovery did open the door to a betterunderstanding of the bodys weight-controlmechanisms. Shortly after the Friedmangroup discovered the hormone, a team ledby Louis Tartaglia of Millennium Pharma-ceuticals in Cambridge, Massachusetts,found the gene for the receptor throughwhich leptin exerts its effects. From there,researchers were able to show that the neu-

rons of the arcuate nucleus, which was al-ready known to be involved in appetite reg-ulation, carry relatively large amounts of thereceptor and might thus be prime targets forleptin in the brain.

Since then, numerous labs have traced theneuronal pathways through which leptin

works in the brain and have shownthat other hormones in-

volved in weightcontrol of-

ten work through the same pathways. Particu-larly important is the arcuate nucleus, whichFriedman describes as the master center: theseat of both the short-term and long-term[weight-regulatory] systems.

The arcuate nucleus, which is located in the hypothalamus, contains two majortypes of neurons with opposing actions. Ac-tivation of one type, which produces peptideneurotransmitters called neuropeptide Y(NPY) and agouti-related peptide (AgRP),stimulates appetite while reducing metabo-lism. In contrast, activation of the other type,

known as POMC/CART neurons, causes therelease of -melanocyte-stimulating hor-mone (-MSH), which inhibits eating.

When fat stores and leptin levels are declining, the NPY/AgRP neurons are activat-ed and the POMC neurons are inhibited, lead-ing to weight gain. Conversely, at least in non-resistant animals, increasing fat stores and lep-tin levels lead to inhibition of the NPY/AgRPneurons and activation of the POMC neurons,resulting in weight loss. The NPY/AgRP andPOMC/CART neurons then send their signalsthrough certain other brain centers to the nu-cleus tractus solitarius of the brain stem, andfrom there to the rest of the body.

One indication of the importance ofthese circuits for weight control comes

from ORahilly and Farooqi and alsofrom Philippe Froguels team at the

Institute of Biology in Lille, France.Although very few cases of hu-man obesity have been linked tomutations in either the leptin orleptin receptor genes, these re-searchers showed a few yearsago that mutations in the recep-tor through which -MSH ex-erts its appetite-inhibiting ef-fects are much more common,accounting for perhaps 5% of

severe obesity cases. Re-searchers are now looking for

compounds that can beef up activa-tion of the receptor in obese people

who dont carry such mutations.Additional targets for potential

antiobesity drugscome from work inwhich researchershave been pinningdown the mecha-nisms by which lep-tin turns up thebodys metabolism. Itapparently does thisat least partly by al-tering the pathwaysthrough which fat ismetabolized. For ex-ample, in work re-ported in Nature in

January 2002, Barbara Kahns team at BethIsrael found that leptin activates a so-calledkinase enzyme in muscle that inhibits acetylcoenzyme A carboxylase, an enzyme thatcatalyzes a key step in fat synthesis.

As a result, the building blocks thatwould otherwise go into fat formation areshifted into a pathway that oxidizes them,providing energy for muscle cells. We didnt say [in the paper] that this causes lean-ness, Kahn says, but it probably does. If ananimal oxidizes its fatty acids instead of stor-ing them, it is going to be leaner.

847www.sciencemag.org SCIENCE VOL 299 7 FEBRUARY 2003

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Central commandcenters. The arcuate

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the opposite effect.These neurons connect with sec-ond-order neurons in other brain centers, and from

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Results from Friedman and his col-leagues suggest that something similar mayhappen in the liver, although there a differ-ent enzyme, stearoyl-CoA desaturase-1(SCD-1), is involved. The Rockefellerteam has evidence that leptin exerts itsantiobesity effects by turning down the ac-tivity of the SCD-1 gene. They found thatthey could protect leptin-deficient micefrom obesity by inactivating the SCD-1gene. The animals also had much highermetabolic rates than ordinary leptin-deficient mice, and their livers stored lessfat. In some way the researchers dont yetunderstand, Friedman says, turning downSCD-1 activity fosters fat metabolism.

Insulin revivalAlthough leptin has received the lions shareof attention as an appetite and metabolismregulator, there are other players, and someof them also work through the arcuate nucle-us. For example, some 25 years ago, DanielPorte of the University of California, SanDiego, and Stephen Woods of the Universityof Cincinnati suggest-ed that the hormoneinsulin acts throughthe brain to regulateweight. Interest in theidea waned somewhatafter the discovery ofleptin, but recent workis reviving it. Insulinis definitely having acomeback, Flier says.

Some of this evi-dence comes fromRonald Kahn (no re-lation to BarbaraKahn) and colleaguesat the Joslin DiabetesCenter in Boston.They stymied insulinaction in the brainsof mice by knocking out the in-sulin receptors located there andfound that the animals overate andbecame fat (Science, 22 Septem-ber 2000, p. 2122).

Insulin receptors occur through-out the brain, but other work hastied the hormones appetite-sup-pressing action directly to the arcu-ate nucleus. Insulin infused intothe brain near the arcuate nucleusinhibits production of the appetite-stimulating NPY, researchers suchas Michael Schwartz of the Uni-versity of Washington, Seattle,have found. And when LucianoRossettis team at Albert EinsteinCollege of Medicine in New YorkCity inhibited production of the in-

sulin receptor specifically in the arcuatenucleus of mice, the animals immediatelyincreased their food intake, the team re-ported in the June 2002 issue of NatureNeuroscience. As Schwartz puts it, aslong as the brain has normal insulin sensi-tivity, you eat less and lose weight. He andothers note, however, that insulins effectsin this regard arent as strong as leptins.

Related studies may lead to antiobesitydrugs that could circumvent obese peoplesresistance to the hormones effects. For in-stance, in experiments described in the April2002 issue of Developmental Cell, BarbaraKahn, Benjamin Neel, also at Beth Israel,and their colleagues knocked out an enzymecalled protein tyrosine phosphatase 1B(PTP1B) in mice. The animals gained muchless weight when fed a high-calorie diet thandid normal controls. This apparently hap-pens because the enzyme inhibits leptin andinsulin signaling in the hypothalamus andother brain areas. Thus, it may be possible tobolster the hormones effects with a PTP1Binhibitor. Barbara Kahn says the enzyme is a

terrific drug target. Otherthan being lean, she says,the mice are pretty normal.

Short-term appetite controlIn addition to getting a han-dle on how the body regu-lates appetite and metabo-

lism over the longhaul, obesity re-searchers are gaininga better understand-ing of how it controlsappetite on a dailybasis. Several yearsago, they identifiedcholecystokinin, apeptide released intothe bloodstream bythe intestine, as asatiety hormoneone that tells us whenweve had enough toeat. Two recentlyidentified appetite-regulating hormonesare now attracting at-tention, both scientif-ically and from thedrug-developmentpoint of view. Theseare ghrelin, an ap-petite stimulant, andPYY, a suppressant.

Kenji Kanagawa,Masayasu Kojima,and colleagues at theNational Cardiovas-

cular Center Research Institute in Osaka,Japan, discovered ghrelin, a peptide producedby the stomach, about 3 years ago. Theyfound that it causes the release of growth hor-mone by the pituitary gland. About a year lat-er, however, Matthias Tschp, then at LillyResearch Laboratories in Indianapolis, Indi-ana, and his colleagues discovered that thehormone has another function as well: Its apotent appetite stimulator.

This discovery helped clear up a majormystery in appetite research, says DavidCummings of the Veterans Affairs PugetSound Health Care System in Seattle,Washington. He points out that people gen-erally want to eat at specific times of day.We want lunch, say, around noon. The trig-ger for that urge wasnt known; it comes up-on us even when theres no food around tostimulate appetite and, Cummings notes, itseemed highly unlikely that leptin could bea meal initiator, because fat stores dontdrop between breakfast and lunch. Butghrelin seems to fit the bill.

For example, when Stephen Bloom ofthe Imperial College Faculty of Medicine inLondon and his colleagues injected ghrelininto human volunteers, it had an amazing-ly powerful effect in increasing the amountof food they subsequently ate, he says. In

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Leptins effects. Because of agene defect, the boy doesntmake leptin, but treatment withthe hormone, begun when he was3.5 years old (top), brought hisweight down to normal levels, asshown at age 8.

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addition, Cummings and his colleagues, in-cluding Puget Sounds Brent Wisse, foundthat ghrelin levels rose an hour or two be-fore a meal and went down to trough levelsafterwardexactly what was predictedfor a meal initiator, Cummings says.Ghrelin may stimulate appetite byworking through the arcuate nucleus, asresearchers have found that it activatesthe NPY/AgRP neurons there.

Although ghrelin is part of the short-term appetite-control system, it can, ifoverproduced, lead to obesity. Prader-Willi syndrome is an inherited conditionthat causes its victims to be extremelyobeseso much so, Cummings says, thatthey often die before age 30 of obesity-related diseases. The Seattle team foundthat the patients have what Cummings de-scribes as the highest ghrelin levels evermeasured in any humans, although the in-creased ghrelin production is apparently anindirect effect of the other chromosomal ab-normalities underlying the disease.

Prader-Willi syndrome is rare, and mostobese humans tend to have lower ghrelin lev-els than people of normal weight, but there isanother way in which the hormone may con-tribute to obesity. The Cummings team re-ported in the 23 May issue of The New Eng-land Journal of Medicine that ghrelin pro-duction increased in people who had lostweight through dieting. The hormone maythus be part of the mechanism that under-mines a dieters ability to shed pounds.

Not every form of weight loss causesghrelin production to go up, however. Anoperation called gastric bypass, which in-volves taking a small portion of the upperstomach and reconnecting it to the small in-testine, seems to be an effective way oftreating extreme obesity. Cummings and hiscolleagues have found that, for reasons notyet understood, ghrelin levels go downand stay downin people who have under-gone the surgery. This might be why theydont try to compensate for their smallerstomachs by eating more frequently.

Meals have to be terminated as well asinitiated. And recent work by Bloomsgroup, in collaboration with that of RogerCone of Oregon Health and Science Uni-versity in Portland, shows that PYY has animportant role to play in that regard. The re-searchers reported in the 8 August 2002 is-sue of Nature that infusions of the hormonelead to decreased eating by mice, rats, andhuman volunteers. The hormone acts in thearcuate nucleus, in this case inhibiting the activity of the appetite-stimulatingNPY/AgRP neurons and stimulating theappetite-suppressive POMC cells.

Whether this recently accumulatedknowledge about the bodys weight-control

systems will pay off in better antiobesitytreatments remains to be seen. But if itdoes, both epidemiology and a new experi-mental study suggest that the reward maybe large: a longer life. In addition to lower-

ing ones risk of deadly obesity-related dis-eases, calorie restriction can extend the life-spans of organisms ranging from the fruitfly to rodents.

Exactly why this is so is not clear. But in

the 24 January issue of Science (p. 572),Ronald Kahn, with Barbara Kahn andMatthias Blher, also at the Joslin DiabetesCenter, report that leanness alone may be allit takes. In earlier work, the Boston workershad genetically modified mice so that their fatcells do not make insulin receptors. Those an-imals have 50% to 70% less fat than unalteredmice, but they otherwise appear healthy.

In the new work, the researchers foundthat the median life span of the modifiedmice increased from about 30 months to 33.5months. Because these animals, despite theirleanness, actually eat more than normalmice, the Boston group concludes that thedecreased fat tissue produced by calorie re-striction, rather than the sparse food intake it-self, is whats important for greater longevity.Given how hard it is to lose weight, keepinga life-span perspective in mind might help usresist adding new pounds. JEAN MARX

849www.sciencemag.org SCIENCE VOL 299 7 FEBRUARY 2003

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Central command. In the arcuate nucleus,NPY/AgRP neurons (green) and POMC/CART neu-rons (red) fight for control of feeding behavior.

N E W S

Obesity DrugPipeline Not So Fat

Drugmakers have been salivating over theprospect of creating antiobesity medica-tions. Obesity is a rising pandemic that in-cludes 60 million adults in the UnitedStates alone, and although most physi-cians champion diet and exercise as thebest way to fight fat, many people are des-perate for an easier way to avoid corpu-lence and consequences such as heart disease, stroke, and diabetes. Its a drug-makers dream.

Prospects looked good in 1994 whenthe discovery of the fat-regulating hor-mone leptin blew open the doors to themolecular world of obesity. The discoverypromised researchers a colorful vista ofnew strategies to work with. They are bad-ly needed; only three fat-busting drugshave clawed their way into the marketplaceand held onamid lawsuits, severe sideeffects, and even, possibly, deaths.

Why arent there more antiobesitydrugs? Quite simply, its hard to treatcomplex diseases, says George Yan-copoulos, chief scientific officer and pres-ident of Regeneron Laboratories in Tarry-

town, New York. Such drugs must tamperwith the biochemistry of metabolism; itsan essential system for survival and thussometimes fatal to disrupt. In addition, ap-petite circuits in the brain use neurotrans-mitters and receptors that control otherbody processes. If you target thesethings, you can get terrible side effects,says endocrinologist Stephen Bloom ofthe Imperial College Faculty of Medicinein London. And that has been the story asobesity pill after hyped obesity pill hascome to market.

And yet research, postleptin, is yield-ing important insights into the bodys castof caloric characters (see p. 846). Somediscoveries are nearing the end of thedrug-development pipeline, enduring thedecade-long time scale of pharmaceuticalresearch and testing. Others are in earlyclinical trials. More are likely to follow;for example, two hot new molecules ap-pear to influence short-term eating pat-terns. Even if today obese individuals orhealth-care providers are frustrated, saysMichael Schwartz of the University of

Eating right and exercising be damned; the search is on for drugs that can control obesity