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UCSD BIBC 102 - A NEAT Way to Control Weight?

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530rural populations of sub-Saharan Africa. Moreover, we do not yet understand themechanism of the protective immuneresponse, the nature of the defect in uis3−GAS, and the role of UIS3 in the intact par-asite. Clearly, uis3−GAS appear to behavedifferently in cultured hepatocytes than dotheir RAS counterparts. The possibility thatthe immune responses provoked by GASand RAS are distinct is exciting andrequires further investigation. The wild-type sporozoite prevents apoptosis of hostliver cells that would otherwise result indestruction of the parasite (13). The behav-ior of uis3−GAS suggests that some colo-nized host cells do undergo apoptosis, andindeed evidence from our laboratories witha different gene-deficient GAS indicatesthat this is the case (15). The possible dele-terious consequences to the host of local-ized hepatocyte apoptosis awaits evalua-tion. It should also be remembered thatmany individuals receiving a GAS vaccineare likely to be immunocompromised—thus, the potential for breakthrough infec-tion with a GAS vaccine must be thor-oughly assessed. Despite this daunting list, the Mueller etal. work is the first concrete demonstration,since the introduction of RAS, that full ster-ilizing immunity against malaria infectioncan be achieved. P. falciparum is amenableto genetic engineering and it should not betoo difficult to produce a nonreverting uis3−P. falciparum strain, which would enable aphase I eff icacy trial in humans to beginsoon. Vaccinating with attenuated infec-tious agents is as old as vaccination itself,and GAS is merely a new take on the oldRAS concept. There is at least one othergene that generates a GAS phenotype whendeleted from the wild-type parasite (15),and surely others will be found. GAS vac-cine efficacy and safety could be improvedby developing more complex GAS strainsthat lack multiple genes in a single parasiteor that have a “GAS mix” containing sporo-zoites each with a different single-genedeletion. Each form of GAS must be evalu-ated for its immunization potential and thebest one, or combination, taken forward tohuman trials. Finally, the availability ofattenuated blood-stage Plasmodium para-sites indicates that an attenuated wholeorganism approach to malaria vaccinationmay be applicable to other stages of the lifecycle of this vicious parasite.References1 A. K. Mueller et al,Nature433, 164 (2005).2. R. S. Nussenzweig et al.,Nature216,160 (1967).3. P. L.Alonso et al.,Lancet364, 1411 (2004).4. A. Morrot, F. Zavala,Immunol. Rev. 201, 291 (2004).5. F. Zavala,Res. Immunol. 142, 654 (1991).6. T. C. Luke, S. L. Hoffman,J. Exp. Biol. 206, 3803 (2003).7. M. J. Gardner et al.,Nature419, 498 (2002).8. J. M. Carlton,Nature419, 512 (2002).9. N. Hall,Science, 307, 82 (2005).10. K. Matuschewski et al.,J. Biol. Chem. 277, 41948(2002).11. T. F. de Koning-Ward et al.,Annu. Rev. Microbiol.54,157 (2000).12. L. F. Scheller, A. F. Azad,Proc. Natl. Acad. Sci. U.S.A.92,4066 (1995).13. P. Leirião et al.,Cell. Microbiol., in press14. A. K. Mueller et al., Molecular Parasitology Meeting,Woods Hole, MA, 19 to 23 September 2004, abstract5H.15. M. R. van Dijk et al., unpublished results.10.1126/science.1108598In a tradition that originated in Babylon4000 years ago, millions of us makeNew Year’s resolutions. Such resolutionsare often to lose weight by exercising moreand eating less. No doubt, before January isout, most of us who swore to take a dailywalk and pass up that extra snack haveslunk back to our old habits. On page 584 ofthis issue, Levine et al. (1) suggest an alter-native strategy for weight control. Theyoffer evidence that differences in posturalhabits account for variations in body weightbetween the lean and the mildly obese.They propose that f idgeting, may be anunusual method of weight control. Six years ago, Levine and co-workersintroduced to Science readers the acronymNEAT, which stands for non-exercise activ-ity thermogenesis (2). NEAT, we were told,is the energy expended by physical activitiesother than planned exercise—sitting, stand-ing, walking, talking, fidgeting, etc. In theiroriginal study, Levine’s group reported thatequally overfed volunteers gained differentamounts of weight, a difference that theyexplained by an individual’s propensity forNEAT (2). Now, in a sequel to this work,Levine et al. attempt to pin down the sourceof NEAT that accounts for this difference inenergy economy (1). These investigatorsoutfitted self-proclaimed “couch potatoes,”both lean and mildly obese, with arrays ofinclinometers and triaxial accelerometersthat continuously measured body postureand movements for 10 days. The authors’main observation is that obese individualsremained seated for about 2.5 hours per daylonger than the lean “couch potatoes,” for anaverage savings of about 350 kcal/day inenergy expenditure (see the figure). As thisenergy saving was not matched by a similardecrease in energy intake, Levine et al. cal-culate that this economy in energy expendi-ture would be sufficient for weight gain inthe mildly obese.In an attempt to determine whether thiseconomy of motion is the cause or the conse-quence of obesity, Levine et al. repeated thestudy. This time, however, obese participantswere put on a diet for 2 months and the leanones were overfed for 2 months, resulting ina loss of 8 kg and a gain of 4 kg, respectively.Although these perturbations were small inmagnitude and short in duration, both thelean and obese maintained their original pos-ture measurements. This suggests thatsedentary habits are biological rather thanenvironmentally determined. Obesity has reached epidemic propor-tions in developed societies, and billions ofdollars are spent on diets and health clubs ina failing effort to control weight. Weight gainis a dynamic process that results from a long-term sustained imbalance between energyintake and energy expenditure. The spectac-ular increase in the prevalence of obesityover the past four decades seems to indicatethat environment, rather than biology, drivesthe epidemic (3). At present, more than two-thirds of Americans are overweight and 25%are obese, and it is expected that the preva-lence of obesity in the United States willreach 40% in 2010—and the rest of theworld is rapidly catching up. Although humans have evolved thriftymechanisms to defend energy stores duringtimes of privation, apparently we have amuch harder time preventing the storage ofexcess energy in times of affluence. Sincethe Second


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UCSD BIBC 102 - A NEAT Way to Control Weight?

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