Background and history of the Department

Reflecting the tradition of research of brown adipose tissue at the Institute, Jan Kopecky was involved in the early studies of the developmental origins and thermogenic function of the tissue (collaboration with B. Cannon and J. Nedergaard, the Wenner-Gren Institute in Stockholm). The role of mitochondrial uncoupling proteins (UCPs) in perinatal development of mammalian tissues was also characterised, including the prove of the significance of their deficiency for postnatal maladaptation of premature human neonates. In collaboration with L. Kozak (the Jackson Laboratory, ME, USA), it has been demonstrated in transgenic mice that obesity could be counteracted by augmenting energy dissipation in white adipose tissue through the use of ectopic expression of UCP1 (J. Kopecky et al, 1995, J. Clin. Invest.). Between 1995 - 2005, mechanisms underlying the lean phenotype of the transgenic mice have been systematically studied at the Department (by J.K., M. Rossmeisl, P. Flachs, P. Janovska, Z. Hodny, I. Syrovy, F. Baumruk, J. Sponarova, O. Horakova, O. Kuda, and other colleagues), revealing the key role of AMP-activated protein kinase (AMPK) in the control of lipid and energy metabolism in adipose tissue.

As a general strategy, experimental findings from studies in mice are complemented by mechanistic studies in vitro, and they are further explored in clinical studies. Collaborations with industrial partners and small companies are essential for effective translational research.

Major achievements and recent interests

1. Description of the beneficial effects of n-3 long-chain polyunsaturated fatty acids of marine origin (omega 3) in the prevention and treatment of obesity and associated metabolic disorders in a mouse model of metabolic syndrome, as well as identification of the underlying mechanisms, namely the activation of adiponectin-AMPK axis, increase of lipid oxidation in white adipose tissue mitochondria, reduction of the low-grade inflammation of the tissue, and inhibition fat cells proliferation [refs. (1-8)].

2. Exploration of the effects of combined interventions, namely the use of dietary omega 3 to augment efficacy of either anti-diabetic drugs (thiazolidinediones; TZD) or calorie restriction (CR) in their beneficial effects on metabolic syndrome phenotypes in mice, [refs. (9-14)].

3. Combination treatment using omega 3 and TZD pioglitazone in a small-scale randomized clinical trial comprising obese and diabetic patients (n=60, ongoing study, in collaborations with T. Pelikanova at the Diabetes Center, IKEM, Prague).

4. Metabolic effects of omega 3 as phospholipids are superior to triglycerides in a mouse model of metabolic syndrome, depending possibly on the modulation of the activity of the endocannabinoid system in white adipose tissue [ref. (15)].

The results concerning the mechanistic aspects of the effects of omega 3 were listed twice among the most significant achievements of the Academy of Sciences of the Czech Republic (in 2009 and 2011).

Available methodologies and approaches

Dietary and pharmacological treatments are performed in laboratory mice (own facility for the animal experiments with a capacity of about 1,500 mice), using a complex platform for in vivo phenotyping in mice (including an indirect calorimetry system, hyperinsulinemic-euglycemic clamps, in vivo analysis of body composition, and behavioral tests), and advanced analytical tools (metabolomic analyses and gene expression screens).

Support

Numerous grants by domestic agencies to J.K. and colleagues, also as a partner in the Center for Applied Genomics (2005-2011; http://www.img.cas.cz/cag/); internationally-funded projects (J.K as P.I.: Howard Hughes Medical Institute; March of Dimes Birth Defect Foundation, Wellcome Trust, EFSD); involvement in the EU-funded projects (6FP, 2005-2010: EXGENESIS and EARNEST; 7FP, 2010-ongoing: BIOCLAIMS and DIABAT); collaborations with companies (Pfizer Inc., CN, USA; Pronova BioPharma, Oslo, Norway; EPAX A.S., Oslo, Norway; Metabolic Solution Development Company, Kalamazoo, USA; Vidia s.r.o., Prague, Czech Republic; and Schoeller Pharma, Prague, Czech Republic).

References

1. Ruzickova,J., Rossmeisl,M., Prazak,T., Flachs,P., Sponarova,J., Vecka,M., Tvrzicka,E., Bryhn,M., and Kopecky,J. 2004. Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 39:1177-1185.

2. Flachs,P., Horakova,O., Brauner,P., Rossmeisl,M., Pecina,P., Franssen-van Hal,N.L., Ruzickova,J., Sponarova,J., Drahota,Z., Vlcek,C., Keijer, J., Houstek, J., and Kopecky, J. 2005. Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia 48:2365-2375.

3. Flachs,P., Mohamed-Ali,V., Horakova,O., Rossmeisl,M., Hosseinzadeh-Attar,M.J., Hensler,M., Ruzickova,J., and Kopecky, J. 2006. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed high-fat diet. Diabetologia 49:394-397.

4. Rossmeisl,M., Jelenik,T., Jilkova,Z., Slamova,K., Kus,V., Hensler,M., Medrikova,D., Povysil,C., Flachs,P., Mohamed-Ali,V., Bryhn M, Berge K, Holmeide AK, and Kopecky J. 2009. Prevention and reversal of obesity and glucose intolerance in mice by DHA derivatives. Obesity 17:1023-1031.

5. Ivan Schothorst,E.M., Flachs,P., Franssen-van Hal,N.L., Kuda,O., Bunschoten,A., Molthoff,J., Vink,C., Hooiveld,G.J., Kopecky,J., and Keijer,J. 2009. Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet. BMC. Genomics 10:110.

6. Kopecky,J., Rossmeisl,M., Flachs,P., Kuda,O., Brauner,P., Jilkova,Z., Stankova,B., Tvrzicka,E., and Bryhn,M. 2009. n-3 PUFA: bioavailability and modulation of adipose tissue function. Proc. Nutr. Soc. 68:361-369.

7. Jelenik,T., Rossmeisl,M., Kuda,O., Jilkova,Z.M., Medrikova,D., Kus,V., Hensler,M., Janovska,P., Miksik,I., Baranowski,M.. Gorski J, Hébrard S, Jensen TE, Flachs P, Hawley S, Viollet B, and Kopecky J. 2010. AMP-activated protein kinase {alpha}2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids. Diabetes 59:2737-2746.

8. Hensler,M., Bardova,K., Jilkova,Z.M., Wahli,W., Meztger,D., Chambon,P., Kopecky,J., and Flachs,P. 2011. The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice. Lipids Health Dis. 10:128.

9. Kunesova,M., Braunerova,R., Hlavaty,P., Tvrzicka,E., Stankova,B., Skrha,J., Hilgertova,J., Hill,M., Kopecky,J., Wagenknecht,M., Hainer, H., Matoulek, M., Parizkova, J, Zak, A., and Svacina, S. 2006. The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese women. Physiol Res. 55:63-72.

10. Kuda,O., Stankova,B., Tvrzicka,E., Hensler,M., Jelenik,T., Rossmeisl,M., Flachs,P., and Kopecky,J. 2009. Prominent role of liver in elevated plasma palmitooleate levels in response to rosiglitazone in mice fed high-fat diet. J. Physiol Pharmacol. 60:135-140.

11. Kuda,O., Jelenik,T., Jilkova,Z., Flachs,P., Rossmeisl,M., Hensler,M., Kazdova,L., Ogston,N., Baranowski,M., Gorski,J., Janovska P, Kus V, Polak J, Mohamed-Ali V, Burcelin R, Cinti S, Bryhn M, and Kopecky J. 2009. n-3 Fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 52:941-951.

12. Kus,V., Flachs,P., Kuda,O., Bardova,K., Janovska,P., Svobodova,M., Jilkova,Z.M., Rossmeisl,M., Wang-Sattler, R., Yu,Z., Illig T, and Kopecky J. 2011. Unmasking differential effects of rosiglitazone and pioglitazone in the combination treatment with n-3 fatty acids in mice fed a high-fat diet. Plos One 6:e27126.

13. Flachs,P., Ruhl,R., Hensler,M., Janovská,P., Zouhar,P., Kus,V., Macek,J.Z., Papp,E., Kuda,O., Svobodova,M.. Rossmeisl M, Tsenov G, Mohamed-Ali V, and Kopecky J. 2011, Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids . Diabetologia 54:2626-2638.

14. Horakova O, Medrikova D, van Schothorst EM, Bunschoten A, Flachs P, Kus V, Kuda O, Bardova K, Janovska P, Hensler M, Rossmeisl M, Wang-Sattler R, Prehn C, Adamski J, Illig T, Keijer J, Kopecky J. 2012. Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese Mice. PLoS ONE - accepted

15. Rossmeisl M, Macek Jilkova Z, Kuda O, Jelenik T, Medrikova D, Stankova B, Kristinsson B, Haraldsson GG, Svensen H, Stoknes I, Sjövall P, Magnusson Y, Balvers MGJ, Verhoeckx KCM, Tvrzicka E, Bryhn B, and Kopecky J. 2012. Metabolic effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: possible role of endocannabinoids. PLoS ONE 7(6): e38834. doi:10.1371/journal.pone.0038834

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