"The increasing incidence of obesity and type 2 diabetes is becoming a major health problem in the European Community and has a considerable economic and social cost. There is therefore an urgent need to understand the basics of these diseases. Physiological processes are subjected to natural daily fluctuations. Interestingly, daily cycles in insulin secretion and glucose tolerance are lost in patients with type 2 diabetes. There is an increased incidence of obesity, metabolic syndrome and cardiovascular disease among shift-workers. These observations pinpoint to a causal relationship between rhythm disturbances and metabolic disorders. Genes of the clock machinery directly influence energy homeostasis as exemplified by Clock mutant mice which are hyperphagic, become obese and diabetic. Metabolic pathways are tightly controlled nuclear receptors. For instance Rev-erbalpha is involved in lipid metabolism, bile acid synthesis and adipogenesis. Interestingly, Rev-erbalpha is also a clock and clock-controlled gene. Therefore Rev-erbalpha may coordinate metabolic processes and peripheral circadian outputs. The objectives of this proposal are: 1. To assess the role of Rev-erbalpha in lipid and glucose homeostasis and the development of insulin resistance and type 2 diabetes. 2. To determine whether Rev-erbalpha plays a role in the intricate link between peripheral circadian molecular clocks and metabolic pathways. This project will provide molecular basis to explain the interaction between circadian rhythms and lipid and glucose metabolism and may therefore suggest possibilities for new therapeutic approaches that take circadian rhythms into account. A long term possibility is the development of more finely tuned, and hopefully more optimal, treatments of dyslipidemia, insulin resistance and type 2 diabetes."