PARTNER 5

Dr. Uberto Pagotto PhD, MD

Universitat di Bologna, Via Massarenti, 9 40138 Bologna, ITALY

See Group Presentation

ROLE AND CONTRIBUTION

Dr. Pagotto will participate in both workblocks. Concerning Biomarkers of obesity (Workblock 2), he will contribute to WP5 with blood samples from the obese patients cohorts recruited at his hospital, and will assist in the validation of candidates of obesity biomarkers searching its functional significance by leading WP6. He will contribute with patient sampling (WP5). He already recruited a total of 500 patients affected by metabolic syndrome (including diabetic subjects) according to the IDF criteria, The Lancet 366, 9491: 1059-1062, 2005. Moreover, a group of controls composed by healthy subjects has been chosen, sex- and age-matched, featured by the absence of any of the IDF criteria. A data base has been designed to handle the collected clinical and laboratory parameters. The routine hematologic and metabolic assessments (including triglycerides, total and HDL cholesterol and glucose – performed after an overnight fasting state) has been used to define the presence of laboratory markers of the metabolic syndrome. A sample of 40 ml of blood has been aliquoted and stored as plasma at – 80°C for the determination of circulating biomarkers at the moment of the diagnosis (naïve state). The patients have been assigned to different therapies in accordance to the original problems: they are subdivided in patients under statins, metformin, glitazones, sibutramine, orlistat. The same amount of blood has been collected regularly at the 3, 6, 9, 12 month of therapy. Due to delay in the commercial approval of Rimonabant in Italy, Dr. Pagotto did not initiate to treat the patients with the first CB1 antagonist, but he will initiate this treatment in a subcohort of patients (100 planned for the first period of 2008). The same occurred in a large group of women (500 subjects vs age and BMI matched control group) affected by polycystic ovary syndrome (PCOS) (a syndrome characterized by hyperandrogenism, insulin resistance and hyperinsulinism frequently associated with obesity). A large data base containing hormonal and metabolic parameters, body composition and anthropometric indexes at basal condition and after different therapies has been generated and correlated with the relevant whole blood biomarkers obtained by ex-vivo analysis. Blood has been obtained by these groups in condition of absence of drugs and after 6 month or 1 year therapy with the common drugs for such disease such as: metformin, orlistat, anti-androgen, sibutramine. He is going to screen the subjects above for the following cytokines: TNF alpha and IL6, complement factors and acute inflammatory markers: Plasminogen Activator Inhibitor-1, (PAI-1) and high-sensitive C Reactive Protein (hsCRP), Adipocytokines: Leptin, Adiponectin, Retinol Binding Protein 4 (RBP4), Fatty acid binding protein 4 (FABP4), and resistin. Moreover, with an instrument of recent acquisition in his lab such as the API Q-TRAP 4000, he will measure in the groups of patients mentioned above endocannabinoids: anandamide, 2-arachidonoyl-glycerol, oleoyletanolamide and palmitoyletanolamide. Dr. Pagotto will assist also in data analysis from adipocyte studies (WP1). In fact, in a fraction of patients mentioned above he got adipose biopsies already processes as mRNA or still intact at -80°C. Concerning his interest on the in vitro part and animal models (WP4). He will contribute with two different models of mice: cannabinoid type 1 receptor knock out and cannabinoid type 1 receptor conditional knock out (animals in which CB1 receptor has been deleted only in the principal neurons of the brain). Both groups of animals are featured by the resistance to develop obesity on high fat diet. He is planning to treat both groups of animals including the two control groups with new drugs known to display an anti-obesity effect such exenatide and inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 to understand the putative interactions between CB1 receptor antagonism and the mode of action of these drugs (WP2 and WP3). The animals are fully characterised in their phenotype by techniques such as real time PCR, western blotting, ELISA and RIA assays. Moreover, lastly the use of Positron Emission Tomography combined with CT-scan fusion to in vivo and longitudinally assess anti-obesity drug effects on Fluoro deoxyglucose uptake in mice target tissues has been validated in his lab. This novel approach (MicroPET/CT) may improve our knowledge on metabolic processes on small animals by helping to evaluate the target tissues, which were previously difficult to identify by using PET alone. Moreover, the combined PET/CT approach will facilitate the understanding of the response to treatment, allowing repeated longitudinal evaluations in the same animal during nutritional or drug interventions (WP2). In such context, he will lead the in vivo phase of biomarkers and therapeutics candidate integration in obesity (first in animals, thereafter in humans): WP7.

SCIENTIFIC PROFILE

Dr. Pagotto is Assistant Professor of Endocrinology at the University of Bologna, S.Orsola-Malpighi General Hospital in the Unit of Endocrinology of the Department of Internal Medicine and Gastroenterology in Bologna, Italy. He earned his medical degree from Padua University Faculty of Medicine. After completing his residency in Endocrinology in Padua, he received a post-doctorate degree in neuroendocrinology at Max-Planck-Institute of Psychiatry in Munich, Germany. In 2000, he was appointed Assistant Professor in Bologna. Dr. Pagotto’s research has been published in 75 peer-reviewed articles. He has received several awards including the 1995 Marius Tausk Award, attributed by the German Society of Endocrinology (DGE) to the best young scientist in endocrinology, and the award attributed to the best young European scientist in basic neuroendocrinology from the European Neuroendocrine Association (ENEA) in 2002. He is recipient of a grant sponsored by the Eli Lilly Foundation International and more recently (2004), he was one of 22 European leaders in obesity and diabetes to receive the 6th Framework project named “Diabesity” sponsored by the European Community. His current research interests include the neuroendocrine control of food intake and metabolism with special regard to the role of cannabinoidergic and ghrelinergic systems in the obesity development. In clinical, his interest is on metabolic syndrome and its determinants in visceral obesity and polycystic ovary syndrome.

CAPACITY TO PROVIDE CONTRIBUTION

The Clinical Unit and the lab of Endocrinology include: 10 MDs and 4 PhDs. We can provide cohorts of normal subjects and/or patients with endocrine and metabolic disorders characterized by obesity and/or insulin resistance and/or hyper- or hypo-androgenic states. Moreover cannabinoid type 1 receptor mice (whole and conditional knock-out) are available to study the potential synergistic effect of cannabinoid system with other anti-obesity drugs involved in the control of energy metabolism.

TEAM MEMBERS

R. Pasquali, MD (M) Full Professor, expert in management of PCOS and obesity;

V. Vicennati MD (F) post-doctoral clinical research assistant, management of obesity;

A. Gambineri MD (F), a post-doctoral clinical research assistant, management of PCOS;

R.De Iasio PhD (F), a post-doctoral basic research assistant, HPLC and API Q-TRAP 4000 expertise;

A. Munarini PhD (F), a post-doctoral basic research assistant, RIA expertise;

C. Cervino PhD (F), a post-doctoral basic research assistant, molecular biology techniques, mice experiments

RECENT RELEVANT PAPERS

1.Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. Journal of Clinical Investigations 112:423-31, 2003.

2. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews 27:73-100, 2006.

 3.Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, Walker BR.Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism 91:2295-302, 2006.

4. Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C, Pagotto U, Pasquali R. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. Journal of Clinical Endocrinology & Metabolism 91:3970-80, 2006.

5. Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grubler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U. Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology 148: 1574-81, 2007