Research Programme Results
Research activities throughout the consortium have achieved, and in some cases exceeded, expectations for the first year. At least 14 novel diabesity genes have been identified in Drosophila that have human homologues. A further 3 potential novel candidate genes have been identified from basic and clinical studies. At month 18 of the project we will select candidates for subsequent validation. Validation strategies have examined key elements in the hypothalamic circuits controlling energy balance and how these are regulated, for example by circulating hormones. To maintain a steady body weight, the hypothalamus has to balance food intake with energy expenditure (in basal metabolism, during exercise and during thermogenesis). Published results to date include several novel findings regarding the mechanisms controlling energy expenditure. Increased obesity in mice lacking the circulating cytokine interleukin-6 (IL-6) appears to result from reduced exercise capacity and reduced energy expenditure during exercise. Moreover, consistent with the anti-obesity effects of IL-6, we have shown that a common polymorphism in the interleukin-6 gene promoter is associated with being overweight. Key elements in the hypothalamic regulation of the thyroid axis, a major regulator of basal metabolism, have been intensively investigated in neuroanatomical studies, revealing the importance of 3 important regulators: the melanocortins 4 receptor, galanin and catecholamines. Novel finding relating to the control of food intake include studies showing that the gut-derived hormone, oxyntomodulin, reduces food intake and body weight in rats via a hypothalamic mechanism. Neuroanatomical studies have also explored the role of the GABA receptor in the regulation of both orexigenic and anorexigenic peptide systems in the hypothalamus. Unpublished target validation work, to date, includes strategies for generating mice transgenic for key signalling molecules, including neurone-selective deletion of key signalling substances. We also have a large body of neuroanatomical and phenotyping data (body weight, food intake, energy expenditure measurements) in novel diabesity models. The regulation of fat mass by key transcription factors, uncoupling proteins, glucocorticoids and by the enzyme 11b-HSD-1 has also been the subject of considerable investigation.
During the 5 years of the project we aim to identify 4-5 new drug targets for the treatment and prevention of diabesity. During the first year of the grant, it was our expectation to identify 4-20 new candidate genes to be considered for subsequent validation. We also expected to provide information about known genes implicated in obesity and type 2 diabetes. As the majority of techniques were already established in the laboratories of the 27 members of this Consortium, we expected to make good progress during the first year and for some of the research to be accepted for publication in scientific journals.
The second full scientific meeting of the consortium will take place in Budapest in April 2005, and this meeting will determine the future development of the project. At this meeting we will select, from the new potential targets identified in year 1, those of greatest promise for further investigation and the key validation criteria these targets. We will exchange information gained during the year, discuss refinements of our strategy, and plan collaborations between consortium members in the light of changing strategic priorities and new opportunities afforded by the technical developments achieved so far.