1. BIOCHEMIE TERMOREGULACE Význam metabolizmu tukové tkáně a svalů pro tvorbu tepla a hromadění tuku v těle Doplňky k biochemii, 2005, 3. část + P. Flachs Jan Kopecký Oddělení Biologie tukové tkáně Fyziologický ústav AV ČR Vídeňská 1083 142 20 Praha 4 kopecky@biomed.cas.cz

2. Energy intake - nutrition Fat stores Basal metabolic rate (BMR) Physical activity Thermogenesis Energy conversion in organism Energy expenditure

3. Thermogenesis in birds and mammals NST, nonshivering thermogenesis = netřesová ter. ST, shivering thermogenesis = třesová ter.

4. Thermogenesis in birds and mammals RMR = resting metabolic rate (resting energy expenditure) Klidový metabolický obrat (klidový energetický výdej) Adaptive thermogenesis Diet-induced T

5. Indirect calorimetry C a H b N c O d S e + x O 2 y CO 2 + z H 2 O Substrates: Glucose, proteins, lipids RMR

6. Calorimeter R 200 ml/min

7. System for indirect calorimetry and telemetry of body temperature and physical acitivity

9. Mitchell, 1961 and 1978

10. Nicholls a Lindberg, 1973 Lin a Klingenberg, 1980

11. Nicholls a Lindberg, 1973 Lin a Klingenberg, 1980

12. Brown fat, 1985 White fat and othere tissues, 1998 Muscle and brown fat, 1998

13. Merklin, Anat. Rec., 1974 Brown fat

14. Thermal homeostasis Body weight control Rothwell a Stock, 1979 Thermogenesis in brown fat, 1963 Drahota, Honová a Hahn, 1968 Pedersen a Grav, 1968

15. Control of thermogenesis in brown fat

16. Induction of UCP1 in brown fat of neonates Mouse Hamster Human Houštěk et al, J. Endocrinol. Met, 1993 Houštěk et al, BBA, 1990 UCP1 antigen Birth Day 7

17. Houštěk et al, J. Endocrinol. Met, 1993 Houštěk et al, BBA, 1990 UCP1 antigen Production of T3 in tissue Birth Day 7 Induction of UCP1 in brown fat of neonates Mouse Hamster Human

18. Common precursor cell Distinct precursor cells Ailhaud et al., 1988

19. Decisive role of PGC-1 in the fate of adipocyte Puigserver and Spiegelman, 2004

20. Energy stores = white fat Light microscopy Electron microscopy Adipocyte

21. Energy storage in white fat High energy content Minimal water content 1 g lipid = 38 kJ Plasticity

22. Všesokolský slet 1920

23. Spartakiáda 1975

24. Všesokolský slet 2000

25. BMI (Body Mass Index) = body weight in kg/ (height in m) 2

26. Kopelman et al, Nature 2000

27. LiverAdipose TissueSkeletal Muscle Adipokines Fatty acids Insulin sensitivity

28. LiverAdipose TissueSkeletal Muscle Adipokines Fatty acids ▲Gluconeogenesis Dyslipidemia Atherosclerosis Mitochondrial damage ▼Performance Pancreatic insufficiency Stroke, ISCH,... ▼Insulin sensitivity

29. Adiponectin Fatty acids Cytokines and metabolites released by adipocytes modulate insulin sensitivity Resistin Leptin IL-6 TNF-  ADMA Visfatin = PBEF

30. Adiponectin Fatty acids Insulin sensitivity Cytokines and metabolites released by adipocytes modulate insulin sensitivity Resistin Leptin IL-6 TNF-  ADMA Visfatin = PBEF Obesity

31. Lipid content Insulin sensitivity

32. Kelley and Mandarino, Diabetes 2000 Lipid Glucose Oxidation „Metabolic inflexibility“ Lean Obese Diabetic

33. Strategies to decrease lipotoxicity Oxidation of lipids in muscle Oxidation of lipids and depression of lipigenesis in adipose tissue

34. Glucose Malonyl CoA De novo FALCFA Oxidation synthesisCoA Esterification TG, DAG Ruderman et al, Endocrinology, 2003 ACC +- CPT-1

35. Glucose Malonyl CoA De novo FALCFA Oxidation synthesisCoA Esterification TG, DAG Ruderman et al, Endocrinology, 2003 AMP-activated protein kinase (AMPK) ACC +- CPT-1 - ACC, acetyl-CoA-karboxyláza CPT, karnitin-palmitoyl-transferáza

36. Glucose Malonyl CoA De novo FALCFA Oxidation synthesisCoA Esterification TG, DAG Ruderman et al, Endocrinology, 2003 AMP-activated protein kinase (AMPK) ACC +- CPT-1 - Lipolysis Glucose uptake Mitochondrial biogenesis

37. Carling, 2004,TIBS 29:18-24 biogenesis of mitochondria

38. Adiponectin Fatty acids Insulin sensitivity Cytokines and metabolites released by adipocytes modulate insulin sensitivity Resistin Leptin IL-6 TNF-  ADMA Visfatin = PBEF

39. Adiponectin Leptin Resistin AMP-activated protein kinase (AMPK) Glu uptake FA oxidation FA synthesis Gluconeogenesis

40. Activators of AMPK Muscle White fat Physical activity++ Fasting+ Leptin+ Adiponectin+ Thiazolidinediones+ +

41. Activators of lipid oxidation Muscle White fat Physical activity++ Fasting+ Leptin+ Adiponectin+ Thiazolidinediones+ +

42. JCI, 2004 Induction of PGC-1  Induction of CPT-1 Induction of mitochondria by TZD in WAT Induction of FA oxidation by TZD in WAT

43. AMPK Phosphorylation ACC ATP/AMP Respiratory uncoupling Stimulation of AMPK in s.c. fat aP2-Ucp1 transgenic mice Matejkova et al FEBS Lett 2004 Kopecky et al et al JCI 1995

44. Resistance to obesity Induction of mitochondria in WAT Reduced accumulation of s.c. fat Control Transgene Induction of FA oxidation in s.c fat

45. PPAR-gama AMPK Phosphorylation HSL ACC FAS ATP/AMP Malonyl-CoA Lipolysis Lipogenesis FA oxidation Exression of SREBP-1 Expression of NRF-1 Mitochondrial content aP2-Ucp1 mice

46. Fatty acids STD HF Rossmeisl et al Obesity Res 2005 LPL

47. Fatty acids * Glucose tolerance test after 2 mo on HFMuscle lipid content STD 3-wk HF 2-mo HF

48. AMPK in adipocytes and its intracellular actions Daval, Fouelle, and Ferré, J. Physiol. 2006

50. Omega 3 polyunsaturated fatty acids (n-3 PUFA) DHA 22:6, n-3 docosahexaenoic acid DHA EPA 20:5, n-3 eicosapenaenoic acid EPA ALA 18:3, n-3  -linolenic a ALA Developmental effects - brain Hypolipidemics Anti-inflammatory effects Reduction of body weight gain Prevention of insulin resistance Direct effects of n-3 PUFA in white fat?

51. HF + EPA/DHA (9% of fat) HF + EPA/DHA (26% of fat) Food intake (kJ/d) 65 ± 3 66 ± 2 62 ± 3 HF diet Different diets Beneficial effects of EPA and DHA in adult mice PREVENTION of OBESITY No effect on food intake Reduced proliferation of fat cells METABOLIC SWITCH in WHITE FAT Induction of mitochondrial biogenesis Induction of FA oxidation Flachs et al, Diabetologia, 2005 2 + 5 weeks schema

52. Protection against Insulin resistance Induction of adiponectin independent on food intake Beneficial effects of EPA and DHA in adult mice Flachs et al, Diabetologia, 2006 HF + EPA/DHA (9% of fat) HF + EPA/DHA (26% of fat) Chow

54. U osob s poruchou glukózové tolerance se podařilo snížit o 60 % riziko vzniku diabetu 2 typu zvýšením fyzické aktivity a úpravou diety Tuomilehto a spol. 2001 N Eng J Med Knowler a spol. 2002 N Eng J Med

55. Energy homeostasis and obesity Jan Kopecký Institute of Physiology Academy of Sciences of the Czech Republic Prague kopecky@biomed.cas.cz