Deletion of Mitochondrial Uncoupling Protein 2 Exacerbates ...
Diagnosing weight disorders by measuring uncoupling proteins
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185 N e w s MOLECULAR MEDICINE TODAY, MAY 1998 Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00 Millenium Pharmaceuticals Inc. (Cambridge, MA, USA) has been granted its first US patent in predictive medicine for methods of diagnosing weight disorders using measurement of uncoupling protein homologue (UCPH) RNA or protein. Scientists at Millenium identified the cDNA that encodes UCPH, which is 50–60% homologous to rodent uncoupling protein (UCP), by screening its sequence database for candidate obesity genes. UCP and UCPH, both mitochondrial inner-membrane transporter proteins, burn excess calories by uncoupling oxidative phosphorylation. This process results in the conversion of excess calories into heat rather than being stored as fat. ‘The respective rodent and human proteins are mediators of non-shivering thermogenesis (NST), an important component of energy expenditure’, explains Louis Tartaglia, senior director of metabolic diseases and oncology at Millenium. ‘UCP is implicated in body weight regulation in rodents, and UCPH probably does the same in humans.’ In rodents, UCP is expressed in brown fat, whereas in humans, who have brown fat only in infancy, UCPH is expressed in several tissues, predominantly in white adipose tissue and skeletal muscle. ‘A large portion of both NST and regulated thermogenesis in man is thought to be mediated by muscle and, to a lesser extent, white adipose tissue’, says Tartaglia. UCPH concentrations are regulated by food intake and increasing fat mass. ‘The discovery of UCPH helps to explain why some people are obese although they don’t overeat’, says Tartaglia. ‘They are simply not producing enough UCPH.’ A tantalizing insight into the role of UCPH in body weight regulation comes from studies in obese (ob/ob and db/db) mice. UCPH, as well as UCP, is found in mice, but mainly in white adipose tissue. UCPH mRNA expression is 4–6-fold higher in the white adipose tissue of obese mice than in lean controls. In Tartaglia’s view, ‘Upregulation of UCPH expression in this context is a compensatory change in which UCPH induction is attempting to act against powerful genetically induced obesity’. The Millenium diagnostic test measures concentrations of UCPH in adipose tissue. ‘People who have low UCPH levels tend to store excess calories as fat, whereas those with high levels burn off the excess’, says Tartaglia. ‘We should be able to learn more about the role of UCPH in mammalian thermogenesis and body weight control from experiments in mouse knockout and transgenic studies.’ One-third of adults in the USA are considered to be obese – i.e. their body mass index is more than 20% above average. As a risk factor for several diseases, among them coronary heart disease, type II (non-insulin-dependent) diabetes and osteoarthritis, obesity is a major public-health problem. Measurement of UCPH levels could help physicians to find out whether a patient is obese through overeating or through inefficient burning of calories. The diagnostic test could thus enable doctors to tailor their recommendations for treatment more closely to the patient’s needs. Therapeutic interventions involving adjustment of UCPH concentrations – still some way off – would enable obese patients to reduce weight by achieving higher levels of activity. Millenium, in collaboration with Hoffmann–LaRoche (Nutley, NJ, USA), is now screening for suitable small molecules, to be taken in pill form, that could do this. ‘Gene therapy is not on the agenda as yet’, notes Tartaglia. Dorothy Bonn Diagnosing weight disorders by measuring uncoupling proteins Rapid update Liquid crystal diagnostics Researchers at the University of California, Davis have come up with a novel method to detect ligand–receptor interactions that could prove invaluable for detecting drugs in blood and for the rapid diagnosis of certain diseases. By using liquid crystal films, they can convert receptor–ligand interactions into an optical signal that can be read with the naked eye. The assays require extremely small amounts of material and can be performed in ambient light without electrical power. V.K. Gupta and colleagues report their findings in the 27 March issue of Science. MMR vaccine off the hook A meeting held on 23 March at the UK Medical Research Council concluded that immunization of infants with the measles–mumps–rubella (MMR) vaccine is not linked to the incidence of autism or Crohn’s disease. The meeting was held at the request of Sir Kenneth Calman, Chief Medical Officer, in response to a study recently published in the Lancet. This study suggested that immunization with MMR correlates with an increased incidence of inflammatory bowel disease and autism. The meeting, which included experts in virology, epidemiology, immunology, paediatrics, child psychiatry, autism, gastroenterology and Crohn’s disease, concluded that the correlation between MMR use and the incidence of Crohn’s and autism did not imply a causative role for the vaccine, and that giving the component vaccines separately was of no benefit. Flu drug on the horizon Glaxo Wellcome has submitted its first application to market zanamivir – a drug that interferes with the life cycle of the flu virus by blocking the viral neuraminidase. The application follows the successful completion of Phase III trials, which showed that the drug not only reduces the duration and severity of flu in infected persons, but also reduces flu-related complications in high-risk patients such as the elderly and those with respiratory and cardiovascular disease. Zanamivir is taken through an inhaler device that delivers the drug directly to the lungs. Catherine Brooksbank
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Transcript of Diagnosing weight disorders by measuring uncoupling proteins
185
N e w sMOLECULAR MEDICINE TODAY, MAY 1998
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00
Millenium Pharmaceuticals Inc. (Cambridge,MA, USA) has been granted its first US patent inpredictive medicine for methods of diagnosingweight disorders using measurement ofuncoupling protein homologue (UCPH) RNA orprotein.
Scientists at Millenium identified the cDNAthat encodes UCPH, which is 50–60%homologous to rodent uncoupling protein (UCP),by screening its sequence database for candidateobesity genes. UCP and UCPH, bothmitochondrial inner-membrane transporterproteins, burn excess calories by uncouplingoxidative phosphorylation. This process results inthe conversion of excess calories into heat ratherthan being stored as fat.
‘The respective rodent and human proteins aremediators of non-shivering thermogenesis (NST),an important component of energy expenditure’,explains Louis Tartaglia, senior director ofmetabolic diseases and oncology at Millenium.‘UCP is implicated in body weight regulation inrodents, and UCPH probably does the same inhumans.’
In rodents, UCP is expressed in brown fat,whereas in humans, who have brown fat only ininfancy, UCPH is expressed in several tissues,predominantly in white adipose tissue andskeletal muscle. ‘A large portion of both NST andregulated thermogenesis in man is thought to bemediated by muscle and, to a lesser extent, whiteadipose tissue’, says Tartaglia. UCPHconcentrations are regulated by food intake andincreasing fat mass. ‘The discovery of UCPHhelps to explain why some people are obesealthough they don’t overeat’, says Tartaglia.‘They are simply not producing enough UCPH.’
A tantalizing insight into the role of UCPH inbody weight regulation comes from studies inobese (ob/ob and db/db) mice. UCPH, as well asUCP, is found in mice, but mainly in white
adipose tissue. UCPH mRNA expression is 4–6-fold higher in the white adipose tissue ofobese mice than in lean controls. In Tartaglia’sview, ‘Upregulation of UCPH expression in thiscontext is a compensatory change in which UCPHinduction is attempting to act against powerfulgenetically induced obesity’.
The Millenium diagnostic test measuresconcentrations of UCPH in adipose tissue.‘People who have low UCPH levels tend to storeexcess calories as fat, whereas those with highlevels burn off the excess’, says Tartaglia. ‘Weshould be able to learn more about the role ofUCPH in mammalian thermogenesis and bodyweight control from experiments in mouseknockout and transgenic studies.’
One-third of adults in the USA are consideredto be obese – i.e. their body mass index is morethan 20% above average. As a risk factor forseveral diseases, among them coronary heartdisease, type II (non-insulin-dependent) diabetesand osteoarthritis, obesity is a major public-healthproblem.
Measurement of UCPH levels could helpphysicians to find out whether a patient is obesethrough overeating or through inefficient burning of calories. The diagnostic test could thus enable doctors to tailor theirrecommendations for treatment more closely tothe patient’s needs.
Therapeutic interventions involvingadjustment of UCPH concentrations – still someway off – would enable obese patients to reduceweight by achieving higher levels of activity.Millenium, in collaboration withHoffmann–LaRoche (Nutley, NJ, USA), is nowscreening for suitable small molecules, to betaken in pill form, that could do this. ‘Genetherapy is not on the agenda as yet’, notesTartaglia.
Dorothy Bonn
Diagnosing weight disorders by measuring uncoupling proteins
Rapid updateLiquid crystal diagnosticsResearchers at the University of California,Davis have come up with a novel method todetect ligand–receptor interactions that couldprove invaluable for detecting drugs in bloodand for the rapid diagnosis of certaindiseases. By using liquid crystal films, theycan convert receptor–ligand interactions intoan optical signal that can be read with thenaked eye. The assays require extremelysmall amounts of material and can beperformed in ambient light withoutelectrical power. V.K. Gupta and colleaguesreport their findings in the 27 March issue of Science.
MMR vaccine off the hookA meeting held on 23 March at the UKMedical Research Council concluded thatimmunization of infants with themeasles–mumps–rubella (MMR) vaccine isnot linked to the incidence of autism orCrohn’s disease. The meeting was held at therequest of Sir Kenneth Calman, ChiefMedical Officer, in response to a studyrecently published in the Lancet. This studysuggested that immunization with MMRcorrelates with an increased incidence ofinflammatory bowel disease and autism. The meeting, which included experts invirology, epidemiology, immunology,paediatrics, child psychiatry, autism,gastroenterology and Crohn’s disease,concluded that the correlation betweenMMR use and the incidence of Crohn’s and autism did not imply a causative role for the vaccine, and that giving thecomponent vaccines separately was of nobenefit.
Flu drug on the horizonGlaxo Wellcome has submitted its firstapplication to market zanamivir – a drug thatinterferes with the life cycle of the flu virusby blocking the viral neuraminidase. Theapplication follows the successfulcompletion of Phase III trials, which showedthat the drug not only reduces the durationand severity of flu in infected persons, butalso reduces flu-related complications inhigh-risk patients such as the elderly andthose with respiratory and cardiovasculardisease. Zanamivir is taken through aninhaler device that delivers the drug directlyto the lungs.
Catherine Brooksbank
