For personal use. Only reproduce with permission from The Lancet Publishing Group.

THE LANCETNeurology Vol 2 January 2003 http://neurology.thelancet.com8

Newsdesk

The more developed world is in the middle of an obesity epidemic.Overconsumption of the wrong typeof food and lack of exercise are oftencited as the main causes, butneuroscientists are beginning to showthat malfunctioning hypothalamicneurons can also lead to obesity.

One molecule that has generated alot of interest is leptin, Barry Levin(Department of Veterans AffairsMedical Center, East Orange, NJ,USA) told delegates at the 32nd annualmeeting of the Society of Neuroscience(Nov 6, 2002, Orlando, FL, USA).Levin’s research team has found thatsome rats are more prone to obesitythan others because of the way theirbrains respond to leptin.

Obesity-prone rats put on weightafter only 1 week of being fed a high fatdiet, but other rats are more resistantto gaining weight, even though plasmaconcentrations of leptin rise in bothgroups. Levin’s group has shown thathypothalamic neurons in obesity-prone rats are less responsive toglucose and leptin, suggesting thatthese animals are predisposed to storecalories when food is available (Am JPhysiol 2002; 283: R941–48). “Theobesity-susceptible rats seem toundergo brain and nervous-systemreorganisations that re-establish newbody-weight set points”, Levin says.“They defend their weight gain whentheir food intake is reduced, and whenfed ad libitum again, regain theirweight back up to the new level.” Thisgenetic predisposition makes itvirtually impossible for obesity-pronerats to lose weight once they becomeobese. “It is likely”, says Levin, “thatbrain development is also affected byboth genetic and environmentalfactors before or shortly after birth sothat maternal obesity can producefurther obesity in geneticallypredisposed offspring.”

Until recently, no one knewwhether leptin acts directly within the hypothalamus to stimulate the gonadotropin-releasing hormone(GnRH)–luteinising hormone (LH)system. However, in recent experim-ents, Hajime Watanobe (InternationalUniversity of Health and Welfare,

Otawara, Tichigi, Japan) perfused thehypothalamus of fasting rats withleptin and showed that GNRH, LH, and � melanocyte-stimulatinghormone (�-MSH) were released (J Physiol 2002; 545: 255–68). “This isthe first time that anyone has demon-strated that leptin can act on both thecell bodies and axon terminals ofGnRH neurons to stimulate the releaseof the neurohormone in vivo, and theyalso suggest that �-MSH may play asignificant intermediary role in linkingleptin and GnRH secretion”,Watanobe told The Lancet Neurology.

Another neuroendocrine product,neuropeptide Y (NPY), is creatinginterest as a regulator of appetite andfood intake. In September, Margaret

Morris and co-workers (University ofMelbourne, Victoria, Australia)showed that hypothalamic neuronsfrom diabetic rats released far less NPYin vitro in response to low glucoseconcentrations than did controlanimals. Next, the researchers inducedhypoglycaemia in vivo with an insulininjection and showed that NPYconcentrations in the paraventricularnucleus decreased in diabetic rats but increased in control animals(Diabetologia 2002; 45: 1332–39). “Westill have much to learn about themechanisms and pathways involved,but this may help to explain why somehuman diabetics do not get the signalto eat when their blood sugar falls:diabetics may experience severehypoglycaemic episodes because theirhypothalamus does not release enoughNPY during hypoglycemia”, saysMorris.

Stephen Bloom’s research group(Imperial College, London, UK) hasshown that peptide YY (PYY), an

agonist of the NPY2 receptor, isreleased from the gut after a meal indirect proportion to the caloriecontent of the meal; intraperitonealinjection of PYY in rats inhibits food intake and reduces weight. “This effect seems to be mediatedthrough the arcuate nucleus: intra-arcuate injection of PYY inhibitsfood intake in rats, and also inhibitselectrical activity of NPY nerveterminals, thus activating adjacentpro-opiomelanocortin neurons thatrelease melanocortin, which decreasesappetite”, explains Bloom. Follow-upexperiments have confirmed that PYYhas similar effects in human beings:infusion of normal postprandialconcentrations of PYY decreasesappetite and reduces food intake by33% after 24 h (Nature 2002; 418:650–54). According to MichaelSchwartz (University of Washington,Seattle, WA, USA) the work ofBloom’s group helps to clarify how thearcuate nucleus translates input fromdiverse hormonal signals intobehavioural and metabolic responsesthat powerfully influence the energy-balance equation. “Changes in bodyweight are communicated to the brainby the hormones leptin and insulin,which inhibit the NPY expressingneurons”, says Schwartz. Ghrelin, thehormone secreted by the stomach assoon as it is empty, can also stimulatefood intake by activating theseneurons. “The new insights are usefulbut many questions remain to beanswered”, warns Schwartz.

Although multiple classes of newantiobesity medications may soon bedeveloped, it is unlikely that any oneapproach will prove to be a magicbullet. However, David Cummings(University of Washington, Seattle,WA, USA) predicts that “customisedcocktails of several agents used incombination with interventions thatreduce signalling by ghrelin or increase signalling at the neuronalmelanocortin, leptin or insulinreceptors may enable obesity to bemanaged much as we now manageother polygenic disorders such ashypertension”.Kathryn Senior

Obesity—is it all in the mind?

Obesity research hots up

Dr

Ray

Cla

rk a

nd M

ervy

n G

off,

SPL

Rights were not grantedto include this image in

electronic media.Please refer to the

printed journal.