Our department is studying physiological regulations of metabolisms and their disturbances in obesity and associated diseases (i.e. Metabolic syndrome). In order to help treat these disorders we explore the influence of drugs, diet and natural substances, namely n-3 polyunsaturated fatty acids of marine origin (omega-3). Our results show the importance of the metabolism of adipose tissue for accumulation of body fat and reveal new possibilities in the prevention and treatment of metabolic disorders linked to obesity by modulating adipose tissue metabolism. We investigate mechanisms that regulate metabolism in health and disease by combining experiments on mice and cell models with clinical studies, and we try to apply new knowledge in clinical medicine. While working with the manufacturers of the tested substances in the Czech Republic and Norway, we investigate the possible use of omega-3 to increase the effect of drugs and other substances in the treatment of selected diseases. Research projects of the department reflect the current grant support and the existence of Research units established during 2015. The "Energy metabolism unit" (PI: J. Kopecký) examines the importance of a "futile" cycle involving the triglyceride hydrolysis and re-esterification of fatty acids in adipocytes of white adipose tissue for resistance to obesity and associated metabolic disorders, namely in the context of calorie restriction, omega-3 administration and cold exposure. The influence of the above manipulations on the formation of lipid mediators, mitochondrial metabolism and proliferation of cells in the adipose tissue is also being characterized. The "Metabolomics unit" (PI: O. Kuda) focuses on the analysis of lipid mediators (eicosanoids) in adipose tissue using the UPLC-MS / MS method, in particular to identify the source of production of various mediators and their effect on metabolism and inflammatory properties of adipose tissue cells (i.e. adipocytes vs. macrophages). New metabolomic methods are also being developed. The "Glucose homeostasis unit" (PI: M. Rossmeisl), by using the method of hyperinsulinemic-euglycemic clamps, analyzes the insulin-sensitizing effects of omega-3 depending on the lipid form (i.e. triacylglycerols vs. phospholipids) of their administration, as well as the involvement of the endocannabinoid system in these effects. We examine the changes in the intestine and their involvement in differential effects of various lipid forms of omega-3 on the whole-body metabolism. Translational potential regarding the beneficial effects of omega-3 on metabolism will also be tested using the transgenic mice expressing the human version of the transcription factor PPARalpha. All the above mentioned Research units are closely collaborating and are engaged in translational research conducted in collaboration with clinical as well as industrial partners.
The Department is subdivided into three Research units with complementary focus, which closely collaborate and are engaged in translational research conducted together with clinical as well as industrial partners.
Projects
White adipose tissue (WAT) is a complex endocrine organ and its low-grade inflammation in obesity contributes to the development of metabolic disorders. Omega-3 polyunsaturated fatty acids (PUFA) play an important role in resolution of inflammation and exert beneficial metabolic effects. In 2014, a class of WAT-born lipid mediators - fatty acid esters of hydroxy fatty acids ( FAHFA) derived from palmitic and stearic acid with anti-inflammatory and anti-diabetic properties was discovered [link]. Our hypothesis is that novel FAHFAs derived from omega-3 PUFA, with anti-inflammatory properties, could be found in mice and humans and that they can beneficially affect adipose tissue metabolism in obesity, especially low-grade inflammation. Using experiments in cell cultures, mice and humans we will explore the structures, effects on WAT inflammation, WAT glucose tolerance and molecular mechanisms of signaling of these new lipokines. Our results will presents a significant advance in research of the mechanisms connecting inflammation, metabolism, and nutritional lipids.
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Long-chain fatty acids of n-3 series (omega-3), mainly EPA and DHA of marine origin, may protect against obesity and exert hypolipidemic effects. While the mechanisms of omega-3’s effects on lipid metabolism in the liver are relatively well described, changes in metabolism in the intestine due to omega-3 are not entirely understood. Previous studies showed that metabolic effects are stronger when omega-3 are administered as phospholipids (Rossmeisl et al., PlosOne 2012). The main goal of this project is to identify the nature of differential metabolic effects of omega-3 depending on the lipid form of their administration (triacylglycerols, phospholipids or wax esters), mainly with regard to the involvement of the intestine in these effects.
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Sufficient plasticity of white adipose tissue allows to adjust appropriately various metabolic processes in response to changing environmental conditions. Metabolic plasticity of adipose tissue is linked with changes in the size and content of cells within the tissue. A hypothesis will be verified that adipose tissue plasticity, namely the proliferative potential of adipose tissue cells, represents an important factor counteracting toxic effects of fatty acids that are released during the breakdown of lipid stores. Reduced ability of the organism to activate these processes could contribute to the development of obesity and its metabolic consequences.
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Minor dietary components with proven biological effects play an important role in the complex treatment strategy of obesity-related diseases, however our knowledge regarding the mechanisms of their action is relatively limited. The aim of this project is to identify novel mechanisms behind the beneficial effects of omega-3 in patients with type 2 diabetes mellitus (DM), i.e. the only dietary component with clearly demonstrated beneficial effects on dyslipidemia and cardiovascular mortality and morbidity in the diabetic patients.
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Metabolic disturbances in obesity are associated with dysregulation of the endocannabinoid (EC) system. We have shown in mice fed an obesogenic high-fat diet that metabolic effects of long-chain omega-3 fatty acids were stronger when supplied in the phospholipid form (omega-3 PL) as compared with triacylglycerols (Rossmeisl et al. 2012. PloS One). These effects were associated with a more efficient modulation of major EC molecules in white adipose tissue (WAT).
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Achievements
Our department is a partner in two EU projects supported through Cooperation program of the European Community (FP7) – BIOCLAMS (2010–2015) and DIABAT (2011–2015).
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Jan Kopecký, MD, PhD won a special prize awarded by the Minister of Education, Youth and Sports for a set of his research group’s papers on the effects of omega-3 fatty acids, published in the last 5 years.
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Set of our papers regarding novel possibilities of the use of sea fish lipids for prevention and treatment of obesity and associated disorders was included on the list of most significant results of Academy of Sciences CR in 2009. Our later article dedicated to combination of omega-3 and mild calorie restriction was included on the same list in 2011.
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Among the five most cited publications of Institute of Physiology published in last 10 years are also three papers of our department.
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Publications
Slámová, Kristýna - Papoušek, František - Janovská, Petra - Kopecký, Jan - Kolář, František
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Adverse Effects of AMP-Activated Protein Kinase alpha 2-Subunit Deletion and High-Fat Diet on Heart Function and Ischemic Tolerance in Aged Female Mice
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Physiological Research. 2016, roč. 65, 1, p. 33-42
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IF = 1.643
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Rohm, M. - Schäfer, M. - Laurent, V. - Üstünel, B. E. - Niopek, K. - Algire, C. - Hautzinger, O. - Sijmonsma, T. P. - Zota, A. - Medrikova, D. - Pellegata, N. S. - Ryden, M. - Kulyte, A. - Dahlman, I. - Arner, P. - Petrovic, N. - Cannon, B. - Amri, E. Z. - Kemp, B. E. - Steinberg, G. R. - Janovská, Petra - Kopecký, Jan - Wolfrun, Ch. - Blüher, M. - Diaz, M. B. - Herzig, S.
An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
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Nature Medicine. 2016, roč. 22, 10, p. 1120-1130
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IF = 30.357
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Pavlišová, Jana - Bardová, Kristina - Staňková, B. - Tvrzická, E. - Kopecký, Jan - Rossmeisl, Martin
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Corn oil versus lard: Metabolic effects of omega-3 fatty acids in mice fed obesogenic diets with different fatty acid composition
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Biochimie. 2016, roč. 124, May, p. 150-162
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IF = 3.017
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Liisberg, U. - Fauske, K. R. - Kuda, Ondřej - Fjare, E. - Myrmel, L. S. - Norberg, N. - Froyland, L. - Graff, I. E. - Liaset, B. - Kristiansen, K. - Kopecký, Jan - Madsen, L.
Intake of a Western diet containing cod instead of pork alters fatty acid composition in tissue phospholipids and attenuates obesity and hepatic lipid accumulation in mice
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Journal of Nutritional Biochemistry. 2016, roč. 33, Jul, p. 119-127
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IF = 4.668
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Kuda, Ondřej - Rombaldová, Martina - Janovská, Petra - Flachs, Pavel - Kopecký, Jan
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Cell type-specific modulation of lipid mediator's formation in murine adipose tissue by omega-3 fatty acids
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Biochemical and Biophysical Research Communications. 2016, roč. 469, 3, p. 731-736
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IF = 2.371
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Kuda, Ondřej - Březinová, Marie - Rombaldová, Martina - Slavíková, Barbora - Pošta, Martin - Beier, Petr - Janovská, Petra - Veleba, J. - Kopecký Jr., J. - Kudová, Eva - Pelikánová, T. - Kopecký, Jan
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Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties
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Diabetes. 2016, roč. 65, 9, p. 2580-2590
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IF = 8.784
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Hu, XQ. - Cifarelli, V. - Sun, SS. - Kuda, Ondřej - Abumrad, N. A. - Su, X.
Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment
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Journal of Lipid Research. 2016, roč. 57, 4, p. 663-673
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IF = 4.368
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Horáková, Olga - Hansíková, Jana - Bardová, Kristina - Gardlo, Alžběta - Rombaldová, Martina - Kuda, Ondřej - Rossmeisl, Martin - Kopecký, Jan
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\\nPlasma Acylcarnitines and Amino Acid Levels As an Early Complex Biomarker of Propensity to High-Fat Diet-Induced Obesity in Mice
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PLoS ONE. 2016, roč. 11, 5, e0155776
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IF = 3.057
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Bardová, Kristina - Horáková, Olga - Janovská, Petra - Hansíková, Jana - Kůs, Vladimír - van Schothorst, E. M. - Hoevenaars, F.P.M. - Uil, M. - Hensler, Michal - Keijer, J. - Kopecký, Jan
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Early differences in metabolic flexibility between obesity-resistant and obesity-prone mice
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Biochimie. 2016, roč. 124, May, p. 163-170
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IF = 3.017
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Duivenvoorde, L. P. M. - van Schothorst, E. M. - Swarts, H. M. - Kuda, Ondřej - Steenbergh, E. - Termeulen, S. - Kopecký, Jan - Keijer, J.
A Difference in Fatty Acid Composition of Isocaloric High-Fat Diets Alters Metabolic Flexibility in Male C57BL/6JOlaHsd Mice
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PLoS ONE. 2015, Vol. 10, 6, e0128515
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IF = 3.057
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