Objective 1

Identify new indications of existing drugs, alone or in combination, with potential anti-obesity efficacy by lowering the fat content and the glucose uptake of abdominal fat cells, which would be expected to improve carbohydrate/lipid metabolism and lower body weight, extracted from the above phenotyped patients. This will be accomplished by screening ex vivo approximately 2.000 known drugs against adipocytes using the novel technology platform “ExviTech” from Vivia Biotech.

Objective 2

Candidates derived from the objective 1 would be evaluated in animal models of obesity. Loss or blockade of body weight gain will be studied in these animal models, and in transgenic mice bearing mutations in genes leading to obese or lean phenotypes. As a pharmacological target of reference we will use cannabinoid CB1 receptor blockers (i.e. Rimonabant), since they are the latest class of drugs authorized for the treatment of obese patients.

Objective 3

Compounds fulfilling objectives of Work Package 1 and Work Package 2 will be evaluated in order to establish their mechanism of action. Molecular biology, biochemistry, cellular physiology, systems physiology with special emphasis on endocrinology, an molecular and systems pharmacology will be used as systematic approaches to elucidate the mechanisms of action of the effective drugs.

Objective 4

To develop the concept of ex vivo Combinatorial Cytomic Biomarkers (CCB) in freshly isolated blood and adipocytes samples of animal models of obesity.Selecting candidates for biomarking obese phenotypes

Objective 5

Discover biomarkers for subsets of obese patients that may correlate with therapeutical outcomes. These biomarkers will be discovered by a novel approach called Combinatorial Cytomic Biomarkers developed by OrphaMed, applied to cells from two physiologically interlinked sources: blood and abdominal-fat samples, extracted from the above phenotyped patients.

Objective 6

Functional signifficance of biomarkers. Use of animal models to link the efficacy of top candidates tested with the modification of Combinatorial Cytomic Biomarkers. Comparison with a drug of proved efficacy (Cannabinoid Receptor antagonist).

Objective 7

Clinical phenotyping of obese patients to identify those that would benefit from existing therapies such as Rimonabant. Generation of a data base with biomarkers useful for phenotyping, adipocyte response to reprofiling drus and clinical data of selected patients. Proposal of new candidates for clinical trials in obesity.