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“Lean gene” may help keep you trim

Sept. 4, 2007
Courtesy Cell Press
and World Science staff

An “anti-obes­ity” gene may explain why some people always stay thin, re­search­ers say. The gene ap­par­ently serves to keep animals lean dur­ing times of plen­ty, and fu­ture weight-cont­rol treat­ments might work by sti­mu­lat­ing it, they add. 

The gene, first dis­cov­ered in flies, al­so keeps worms and mice trim, ac­cord­ing to a re­port in the Sep­tem­ber is­sue of the re­search jour­nal Cell Me­tab­o­lism. If the gene works si­m­i­larly in hu­mans, the find­ings could lead to a new weap­on against our bur­geon­ing waist­lines, ac­cord­ing to the re­search­ers.

An­i­mals with­out a work­ing copy of the gene, known as Ad­i­pose, be­come obese and dia­betes-prone, while those with in­creased Adp ac­ti­vity in fat tis­sue be­come slim­mer, sci­ent­ists found. More­o­ver, the gene’s “dose” seems to de­ter­mine how slen­der an an­i­mal turns out to be.

If treatments could stimulate this gene “even just a lit­tle bit, you might have a ben­e­fi­cial ef­fect on fat,” said Jon­a­than Graff of the Un­ivers­ity of Tex­as South­west­ern Med­i­cal Cen­ter in Dal­las, Texas. He noted that peo­ple of­ten be­come over­weight very grad­u­al­ly—adding just one or two pounds a year. “After 30 years, that’s a lot.”

While worms and flies are rou­tinely stud­ied as mod­els of hu­man health and dis­ease, that trend has been less true in fat bi­ol­o­gy, Graff said. That’s be­cause un­like mam­mals, worms and flies store their fat in mul­ti­func­tion­al cells rath­er than in ded­i­cat­ed fat cells known as adipocytes. How­ev­er, those dif­fer­ences did­n’t pre­clude the pos­si­bil­ity that the an­i­mals might use si­m­i­lar genes to ac­com­plish their fat stor­age goals, he added.

Graf­f’s team found that worms lack­ing Adp ac­ti­vity be­came fat, al­though they ap­peared to be oth­er­wise healthy and fer­tile. In­deed, an­oth­er sci­ent­ist, Winifred Doane, had found a nat­u­rally oc­cur­ring strain of plump flies in Ni­ge­ria al­most 50 years ago that car­ried a muta­t­ion in their Adp gene. The flies lived in a cli­mate marked by cy­cles of fam­ine, where they may have ben­e­fit­ed from be­ing highly ef­fi­cient at fat stor­age, Doane had sug­gested.

Graff and his col­leagues pro­duced a strain of mu­tant flies like those that Doane had found years ear­li­er. They found that the mu­tant flies were in­deed fat and al­so had trou­ble get­ting around. Flies with only one copy of the Adp muta­t­ion fell some­where in be­tween the fat and nor­mal flies, ev­i­dence that the gene’s ef­fects are “dose de­pen­den­t,” they re­ported.

Treat­ments that in­creased Adp in the in­sects’ fat tis­sue led them to lose weight, sug­gest­ing the gene works with­in fat cells them­selves. In mice in which the gene funct­ioned in in fat-storing tis­sues, the same pat­terns emerged.  “We made mice that ex­pressed Adp in fat-storing tis­sues, and lo and be­hold... they were skin­ny,” Graff said. They “weighed less with markedly less fat—and their fat cells were small­er.” Smaller fat cells usu­ally trans­late in­to bet­ter met­a­bol­ic func­tion, he said, in­clud­ing bet­ter blood sug­ar con­trol.

The search for mo­le­cules un­der­ly­ing weight gain and poor blood sug­ar con­trol “has tak­en on ad­di­tion­al ur­gen­cy due to the re­cent dra­mat­ic in­crease in obes­ity and di­a­betes,” Graff said. But in a mod­ern world where many peo­ple have es­sen­tially un­lim­it­ed ac­cess to food, it’s a won­der that even more peo­ple aren’t over­weight, he added. If this gene plays a si­m­i­lar role in hu­mans, “it may be that some peo­ple’s Adp works very well.”


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Researchers have reported the discovery of a gene that helps keep its bearers skinny. The “antiobesity” gene has apparently been keeping critters lean during times of plenty since ancient times, researchers said. The gene, first discovered by another team in flies, also keeps worms and mice trim, according to the new report in the September issue of the research journal Cell Metabolism. If the gene works similarly in humans, the findings could lead to a new weapon against our burgeoning waistlines, according to the researchers. Animals without a working copy of the gene, known as Adipose, become obese and diabetes-prone, while those with increased Adp activity in fat tissue become slimmer, the researchers found. Moreover, the gene’s “dose” seems to determine how slender an animal turns out to be. “Maybe if you could affect this gene, even just a little bit, you might have a beneficial effect on fat,” said Jonathan Graff of the University of Texas Southwestern Medical Center, noting that people often become overweight very gradually—adding just one or two pounds a year. “After 30 years, that’s a lot.” While worms and flies are routinely studied as models of human health and disease, that trend has been less true in fat biology, Graff said. That’s because unlike mammals, worms and flies store their fat in multifunctional cells rather than in dedicated fat cells known as adipocytes. However, those differences didn’t preclude the possibility that the animals might use similar genes to accomplish their fat storage goals, he added. In the new study, Graff’s team found that worms lacking Adp activity became fat, although they appeared to be otherwise healthy and fertile. The researchers scoured the genetic database in search of related genes and found one with “tremendous” similarity in flies. Indeed, another scientist, Winifred Doane, had found a naturally occurring strain of plump flies in Nigeria almost 50 years ago that carried a mutation in their Adp gene. The flies lived in a climate marked by cycles of famine, where they may have benefited from being highly efficient at fat storage, Doane had suggested. To explore Adp’s function even further, Graff and his colleagues produced a strain of mutant flies like those that Doane had found years earlier. They found that the mutant flies were indeed fat and also had trouble getting around. Flies with only one copy of the Adp mutation fell somewhere in between the fat and normal flies, evidence that the gene’s effects are “dose dependent,” they reported. Treatments that increased Adp in the insects’ fat tissue led them to lose weight, evidence that the gene operates within fat cells themselves. In mice that expressed the gene in fat-storing tissues, the same patterns emerged. “We made mice that expressed Adp in fat-storing tissues, and lo and behold, what happened”“ Graff said. “They were skinny—weighed less with markedly less fat—and their fat cells were smaller.” Smaller fat cells usually translate into better metabolic function, he said, including better blood sugar control. “It’s a striking conservation of genes that restrain fat,” he said. While fat storage is an important mechanism for getting through lean times, “too much fat in times of plenty has deleterious consequences.” The search for molecules underlying weight gain and poor blood sugar control “has taken on additional urgency due to the recent dramatic increase in obesity and diabetes,” Graff said. But in a modern world where many people have essentially unlimited access to food, it’s a wonder that even more people aren’t overweight, he added. If this gene plays a similar role in humans, “it may be that some people’s Adp works very well.”