אסף רודיך M.D., Ph.D. המחלקה לביוכימיה קלינית והמרכז לתזונה הפקולטה למדעי הבריאות אונ' בן-גוריון

1. מאזן האנרגיה וההוצאה האנרגטית - הבסיס לטיפול בשינויי אורח חיים (פרקים נבחרים...) אסף רודיך M.D., Ph.D. המחלקה לביוכימיה קלינית והמרכז לתזונה הפקולטה למדעי הבריאות אונ' בן-גוריון rudich@bgu.ac.il

2. בקרת משקל הגוף:פשוט מאוד.... זה מסובך! מטרות: • אם זה כ"כ פשוט, למה זה בעצם כ"כ מסובך? • מנגנונים בסיסיים בבקרת צריכת האנרגייה (אכילה) • מנגנונים בסיסיים בבקרת ההוצאה האנרגטית • דוגמאות ליחסי הגומלין המורכבים בין הצריכה האנרגטית וההוצאה האנרגטית • איך סוכרת מסבכת עוד את העניינים...

3. Simple: The energy balance and the laws of thermodynamics Energy intake Energy expenditure

4. The energy balance: Energy intake Energy expenditure • Involuntary: • BMR (basal metabolic rate) • TEF (Thermic effect of food) • Voluntary (activity): • NEAT (non-exercise activity thermogenesis) • ET (exercise thermogenesis) Food intake (calories): Nutrients: lipids Carbohydrates proteins

5. The control of food intake • Complex process: Metabolic, Neuro-endocrine, Mental (including mood), Social, Cultural factors • Complex afferent signals (orexigenic Vs anorexigenic): • hunger versus satiety (feeding frequency); • “fullness” signals (meal size); • energy abundance signals (short/long term); • food composition signals (olfaction); • Mood, social, cultural • Mediators: • Neuronal: • Central: Hypothalamus, brain stem, Area Postrema, “reward” centers, Cortical centers • peripheral: Vagus • Hormonal (pancreas, fat tissue, GI)

6. Hypothalamus = anorexigenic orexigenic =

7. food-seeking behaviour ** MC-R4 (melanocortin Receptor 4) ** αMSH NPY (Orexogenic signal) (Anorexogenic signal) ** The Arcuate Nucleus of the Hypothalamus: integrator of orexigenic and anorexigenic signals

8. food-seeking behaviour αMSH NPY (Orexogenic signal) (Anorexogenic signal) Summary: GI, pancreatic and adipose signals for hypothalmic regulation of food intake

9. Hypothalamus Adipose tissue = anorexigenic orexigenic =

10. Adipostatic action of Leptin:Leptin signals fat-storage sufficiency leptin (Nature 404: 661, 2000)

11. 2. Neuroplasticity (h) 3. Developmental Excitatory synapses Inhibitory synapses + - + - - - + + Leptin effect in the arcuate nucleus of the hypothalamus: 1. Direct (rapid) effect food-seeking behaviour αMSH NPY (Orexogenic signal) (Anorexogenic signal) (Science 304:63-4, 2004)

12. Hypothalamus Adipose tissue GI tract • Does insulin resistance develop in the brain? • Does it mediate reduced anorexigneic signal? • Can common mechanisms underlie insulin and leptin resistance??? Pancreas = anorexigenic orexigenic =

13. The energy balance: Energy intake Energy expenditure • Involuntary: • BMR (basal metabolic rate) • TEF (Thermic Effect of Food) • DIT (Diet-Induced Thermogenesis) • Voluntary: • NEAT (non-exercise activity thermogenesis) • ET (exercise thermogenesis) Food intake (calories): Nutrients: lipids Carbohydrates proteins Obligatory Vs. Facultative (adaptive)

14. Muscle Brown Adipose Tissue White Adipose Tissue Acetylcholine (central) Norepinephrin (central) Thyroid hormone GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Components of Total Daily Energy Expenditure (TDEE) Facultative (adaptive) thermogenesis 30% (20 to >100) Exercise thermogenesis 6-12 % • Essential thermo. • Endothermic thermo. Diet-induced thermogenesis Obligatory thermogenesis ~ 60%

15. ההוצאה האנרגטית: גילגול אנרגייה האגורה במזון ("שריפת" המזון) לייצור ATP, והאנרגייה האגורה ב-ATP ל"עבודה" "שריפת המזון" ATP ייצור ATP ניצול פוטנציאל אלקטרו-כימי חומר מחזר מיטוכונדריה!!

16. Noradrenalin Thyroid hormone mitochondria נוראדרנלין והורמון הטירואיד מבקרים את המספר והיעילות האנרגטית של מיטוכונדריות NRF – nuclear respiratory factor mtTF-A – mitochondrial trascription factor A PGC-1 – PPARγ co-activator 1 CREB – cAMP responsive element binding protein DII – Thyroxine 5’-deiodinase type 2 mtTF-A

17. The energy balance Energy intake Energy expenditure צריכת האנרגייה מבקרת את ההוצאה האנרגטית

18. השפעת הצריכה האנרגטית על ההוצאה האנרגטית: עדות לעצמת מנגנוני הבקרה של מאזן האנרגייה

19. Body mass Energy intake and energy expenditure exhibit complex inter-relations Energy intake Energy expenditure • Involuntary: • BMR (basal metabolic rate) • TEF (Thermic effect of food) • Voluntary (activity): • NEAT (non-exercise activity thermogenesis) • ET (exercise thermogenesis) Food intake (calories): Nutrients: lipids Carbohydrates proteins Processes: Eating initiation (frequency) Satiety sensation / appetite regulation (meal size) Diet composition

20. ~20% ~60% decrease בקרת ההוצאה האנרגטית ע"יצריכת האנרגייהאיננה מלאה: משקל הגוף בכל-זאת משתנה

21. הבדלים בין-אישיים במידת ההשפעה של צריכת אנרגייה על הוצאת האנרגייה: תרומת הגנטיקה • identical, severe caloric deficit in 14 female monozygotic twins: • weight loss of 5.9 – 12.4 Kg • High correlation in the change within twin pairs (r=0.88), but much less between pairs • (Int J Obes 25: 533, 2001) Genetics plays an important role in the association between Energy intake and Energy expenditure: The ability to regulate the coupling of food intake, ATP production, and ATP utilization • a 1000 kCal over-eating in 12 male monozygotic twins for 100 days: • weight gain of 4.3 – 13.3 Kg • within twin pairs variability 6-fold lower than between pairs variability • (NEJM 322: 1477, 1990)

22. Nutrient combustion results in fixes amount of reducing equivalent Entering reducing equivalent into the Mt through the glycerol phosphate shuttle versus aspartate-malate shuttle Fixed amount of ATP is produced for a certain amount of protons pumped out of the Mt Uncoupling proteins The coupling, uncoupling, and futile cycling of reactions in energy metabolism: Fuel combustion ATP synthesis ATP utilization for work פוטנציאל אלקטרו-כימי חומר מחזר

23. (oxidation) NADH + H+ + ½O2 NAD+ + H2O DG = -52.7 kCal/mol3ADP +3Pi 3ATPDG = 21.9 kCal/mol (phosphorylation) Coupling the electron transport chain to ATP synthesis

24. Nutrient combustion results in fixes amount of reducing equivalent Entering reducing equivalent into the Mt through the glycerol phosphate shuttle versus aspartate-malate shuttle Fixed amount of ATP is produced for a certain amount of protons pumped out of the Mt Uncoupling proteins The coupling, uncoupling, and futile cycling of reactions in energy metabolism • Fixed amount of ATP is required for fixed amount of biological activity • Futile cycles • higher Vs lower efficiency isoforms

25. ה"נטייה להשמנה" תלוייה במידת הצימוד וביכולת להפר את הצימוד שבין ייצור אנרגייה מהמזון, ייצור ATP וניצול ATP Energy +ADP +Pi Food Combustion ATP +ADP +Pi + WORK Synthesis Ion transport Muscle work

26. Energy intake Energy expenditure השפעה גדולה של EI על EE: יכולת הפרת צימוד גדולה בין ייצור אנרגייה לעבודה השפעה קטנה של EI על EE: יכולת הפרת צימוד קטנה בין ייצור אנרגייה לעבודה

27. משמעויות טיפוליות – לא פרמקולוגי Energy intake Energy expenditure • Increasing Exercise: • direct increase in TEE • indirect, EXTENDED increase in TEE through elevation in BMR (Thyroid, Sympathetic - UCP) • prevents the adaptive decrease in BMR during caloric restriction • Food composition choices: • High protein? Low carb? (Increase satiety?) • Decreasing energy extraction from food – dairy products? • Decrease highly calorie-dense foods • Decrease soft drinks • GI microbial flora: • Decreasing energy extraction from food (Nature 444: 1027, 2006) • Increasing NEAT: • life style choices • work environment engineering • cultural change • Increasing DIT: • Low quality protein?

28. משמעויות טיפוליות – פרמקולוגיה Energy intake Energy expenditure • Increasing BMR, non-voluntary components of NEAT • beta 3 adrenergic agonists • Increasing anorexigenic, decreasing orexigenic signals: • GLP1 analogues (Extenetide) and DPP4 inhibitors (Citagliptin) • Metformin  - Ghrelin • Decreasing reward signals to food: • CB1 inhibitors (Rimonabant) • Decreasing nutrient absorption: • Pancreatic lipase (Orlistat) • - A glucosidase inhibitors (Orlistat)

29. Delayed increase in insulin sensitivity (risk of hypo up to 72 h from exercise) Diabetics may be particularly resistant to weight loss by caloric restriction ומה בסוכרת? Energy intake Energy expenditure • Increasing Exercise: • direct increase in TEE • indirect, EXTENDED increase in TEE through elevation in BMR (Thyroid, Sympathetic - UCP) • prevents the adaptive decrease in BMR during caloric restriction • Food composition choices: • High protein? Low carb? (Increase satiety?) • Decreasing energy extraction from food – dairy products? • Decrease highly calorie-dense foods • Decrease soft drinks Diabetics seem to have increased BMR compared to weight-matched non-diabetics: increase GNG? Direct effect of hyperglycemia? Glucosuria – abnormal loss of calories • Increasing NEAT: • life style choices • work environment engineering • cultural change • Increasing DIT: • Low quality protein?

30. Thank you ! Kibbutz Ruhama, Israel (photo: Zvia Rudich)