Background and history of the Department
         Prevention and treatment of obesity is an increasing problem of health care. Obesity represents a health risk due to its frequent association with cardiovas cular diseases, non-insulin-dependent diabetes mellitus, hypertension, and hyper lipidemia (metabolic syndrome). The health risk of obesity depends also on the distribution of adipose tissue in the body. Especially harmful is excessive accumulation of the abdominal fat. It is probable that propensity to obesity and development of the metabolic syndrome are affected, in part, by nutritional and other environmental factors acting around birth (metabolic imprinting).
Work performed at the Department seeks to characterize the biochemical pathways leading to metabolic energy efficiency, which underlie obesity and body fat distribution. Special attention is paid to the metabolism of adipose tissue itself. This direction reflects the early studies on the thermogenic brown adipose tissue, namely the work of Z. Drahota and colleagues at the Institute. Since 1974, J. Kopecký (J.K.) has been was involved in these studies. During 1980 - 88, J.K. contributed (together with J. Houštěk and other colleagues) towards the characterisation of the perinatal development of brown fat in several mammalian species. In 1990, in collaboration with the scientists at the Wenner-Gren Institute in Stockholm, the differentiation of brown adipocytes in vitro was described. Other scientists discovered that thermogenesis in brown fat relied on uncoupling protein 1 (UCP1). This protein induces proton leak in mitochondria and it is a marker of brown adipocytes.
         In order to test the hypothesis whether mitochondrial uncoupling in white fat could reduce body fat, transgenic (aP2-Ucp1) mouse with ectopic UCP1 in white fat was developed at the Jackson Laboratory (USA), in collaboration between J.K. and L.P. Kozak. As predicted, aP2-Ucp1 mice were resistant to genetically determined obesity. Unexpectedly, the transgene also affected body fat distribution with reduction of the subcutaneous and a negligible effect on the gonadal fat in the abdomen. In 1993, a breeding colony of the aP2-Ucp1 mice has been established at the Institute of Physiology in Prague and the mice are used for studies (see below). The laboratory was established in 1992 as the Department of Cell Culture (renamed in 1999 as the Department of Adipose Tissue Biology). The following scientists helped to shape the laboratory team and brought important expertise, in the cell culture work and in biochemistry: MUDr Marie Baudyšová, PhD, RNDr Milada Horáková, PhD, and RNDr Ivo Syrový, PhD, DSc. These scientists retired during 1998-2001. The work on aP2-Ucp1 mice served as a vehicle to introduce modern methods and purchase the appropriate equipment for biochemistry and molecular biology. Financial resources from domestic grants and resources abroad (Howard Hughes Medical Institute, March of Dimes of Birth Defects Foundation, The Wellcome Trust, and integrated projects of EU - EXGENESIS a EARNEST). Collaborations with large companies is also important (Pfizer, USA; Pronova Biocare, a.s., Norway). The work is increasingly based on the involvement of pregraduate and PhD students. Since 2000, the Department was associated with the Center for Integrated Genomics, and since 2005 with the Center for Applied Genomics (http://www.img.cas.cz/cag/).

Specific aims of the research
         Between 1995 and 2000, the main goal was to verify whether respiratory uncoupling in white fat could reduce fat content, as indicated by the phenotype of the aP2-Ucp1 transgenic mice. This goal received a substantial support in 1997, by the discovery of UCP2 (a close homologue of UCP1). Because white fat contains UCP2, and UCP2 is linked to obesity, respiratory uncoupling in adipocytes may be an important biological mechanism controlling adiposity. More recently, importance of energy charge and AMP-activated protein kinase (AMPK)in adipocytes in the control of metabolic properties of fat cells and fat accumulation are studied under naturally occuring conditions like during fasting and other circumstances. The role of UCPs in perinatal development of mammalian tissues is also studied with a special focus on premature human neonates. We seek to understand whether UCP3 is involved in metabolic imprinting. Specific area of reserch concerns the mechanisms involved in the effect of polyunsaturated fatty acids of marine origine (n-3 PUFA) on energy matabolism and insulin sensitivity.

Results
1. Respiratory uncoupling in adipocytes could reduce accumulation of body fat in mice.
2. Respiratory uncoupling in white fat stimulates mitochondrial biogenesis, reduces in situ lipogenesis and catecholamine-induced lipolysis, and increases metabolic rate, via stimulating AMP-activated protein kinase in adipocytes.
3. Liver in the major site of UCP2 expression in mammalian foetuses, expression of UCP2 in the liver is located in Kupffer cells and declines postnatally, suggesting a role for UCP2 in immune system and/or haematopoiesis.
4. UCP3 gene in human skeletal muscle is recruited postnatally by nutritional lipids and the recruitment is abolished in newborns delivered before 26 weeks of gestation.
5. Prevention of obesity and insulin resistance by n-3 PUFA is related to induction of lipid oxidation in white adipose tissue and adiponectin release from fat cells.

Other activities
Organization of the 13th European Congress on Obesity in 2004 in Prague and of its satelite symposium: Indirect Calorimetry in Rodent Models: Applications to Studies of the Metabolic Syndrome.

Publications