Diagnosing weight disorders by measuring uncoupling proteins

Abstract

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.