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

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Presentation on theme: "אסף רודיך M.D., Ph.D. המחלקה לביוכימיה קלינית והמרכז לתזונה הפקולטה למדעי הבריאות אונ' בן-גוריון מאזן האנרגיה וההוצאה האנרגטית - הבסיס."— Presentation transcript:

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

2 בקרת משקל הגוף: פשוט מאוד.... מטרות: 1.אם זה כ"כ פשוט, למה זה בעצם כ"כ מסובך? 2.מנגנונים בסיסיים בבקרת צריכת האנרגייה (אכילה) 3.מנגנונים בסיסיים בבקרת ההוצאה האנרגטית 4.דוגמאות ליחסי הגומלין המורכבים בין הצריכה האנרגטית וההוצאה האנרגטית 5.איך סוכרת מסבכת עוד את העניינים... זה מסובך!

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

4 The energy balance: Energy expenditure - Involuntary: - BMR (basal metabolic rate) - TEF (Thermic effect of food) - Voluntary (activity): - NEAT (non-exercise activity thermogenesis) - ET (exercise thermogenesis) Energy intake 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 The Arcuate Nucleus of the Hypothalamus : integrator of orexigenic and anorexigenic signals food-seeking behaviour NPY (Orexogenic signal) αMSH (Anorexogenic signal) ** ** MC-R4 (melanocortin Receptor 4)

8 The Arcuate Nucleus of the Hypothalamus : integrator of orexigenic and anorexigenic signals food-seeking behaviour NPY (Orexogenic signal) αMSH (Anorexogenic signal) - Homozygous POMC mutations cause early onset obesity, adrenal insufficiency, red hair pigmentation - MSH receptor 4 (MC4) mutations account for ~6% of severe early onset obesity, whereas a “hyperactive” MC4 mutant negatively associates with obesity - Obesity can result from normal POMC transcription and translation, but impaired post- translational processing due to deficient prohormone convertase 1. Genetic evidence for the central role of the POMC-MSH as a major anorexigenic signal: MC4 agonists as appetite suppressants??

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

10 Adipose tissue Hypothalamus = anorexigenic orexigenic =

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

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

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

14 The energy balance: 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) Energy intake Food intake (calories): Nutrients: lipids Carbohydrates proteins Obligatory Vs. Facultative (adaptive)

15 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE)

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

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

18 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 Noradrenalin Thyroid hormone mitochondria

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

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

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

22 בקרת ההוצאה האנרגטית ע"י צריכת האנרגייה איננה מלאה: משקל הגוף בכל-זאת משתנה ~60% decrease ~20%

23 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) - 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) 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

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: Fuel combustionATP synthesisATP utilization for work חומר מחזר פוטנציאל אלקטרו-כימי

25 Coupling the electron transport chain to ATP synthesis NADH + H + + ½O 2 NAD + + H 2 O  G = kCal/mol 3ADP +3Pi 3ATP  G = 21.9 kCal/mol (oxidation) (phosphorylation)

26 The coupling, uncoupling, and futile cycling of reactions in energy metabolism 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 Fixed amount of ATP is required for fixed amount of biological activity - Futile cycles - higher Vs lower efficiency isoforms

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

28 Energy expenditure Energy intake 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

29 משמעויות טיפוליות – לא פרמקולוגי Energy expenditure Energy intake -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 -Increasing NEAT: - life style choices - work environment engineering - cultural change -Increasing DIT: - Low quality protein? - 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)

30 משמעויות טיפוליות – פרמקולוגיה Energy expenditure Energy intake - 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) - Increasing BMR, non- voluntary components of NEAT - beta 3 adrenergic agonists

31 ומה בסוכרת ? Energy expenditure Energy intake -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 -Increasing NEAT: - life style choices - work environment engineering - cultural change -Increasing DIT: - Low quality protein? - Food composition choices: - High protein? Low carb? (Increase satiety?) - Decreasing energy extraction from food – dairy products? - Decrease highly calorie- dense foods - Decrease soft drinks 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 Diabetics seem to have increased BMR compared to weight-matched non- diabetics: increase GNG? Direct effect of hyperglycemia? Glucosuria – abnormal loss of calories

32 Kibbutz Ruhama, Israel (photo: Zvia Rudich)

33 GLP-1 –based new medications GLP-1R agonists DPP-4 inhibitors Lancet, 368: 1696, 2006

34 Characteristics of the maintenance of body weight: the end-product of energy balance - Does not escape the laws of thermodynamics - Weight maintenance requires a tight regulation of energy balance over time: -even a persistent 1% difference between energy expenditure and energy intake will lead to a 1 Kg/year change in body weight (40 Kg gain between ages 20 and 60) - (existing methods to measure EE and EI can hardly detect reliably a 5% difference…) - Body weight fluctuates: - Short-term (day to day) fluctuations of 0.5% - Long-term, life-time fluctuations of 7-20%

35 How is heat generated? Two basic types of thermogenic mechanisms: 1.ATPase type - ATP consuming reactions - Energy required for ATP synthesis 2. Uncoupling type - Uncoupling between electron transfer and ATP synthesis

36 Aspartate-Malate shuttle versus glycerol-3-phosphate shuttle NADH (cytosol)  NADH (Mt)  3ATP NADH (cytosol)  FADH2 (Mt)  2ATP

37 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE)

38 Obesity: energy imbalance Energy expenditure Energy intake Food intake (calories): Nutrients: lipids Carbohydrates proteins Processes: Eating initiation (frequency) Satiety sensation / appetite regulation (meal size) Diet composition - Involuntary: - BMR (basal metabolic rate) - TEF (Thermic effect of food) - Voluntary (activity): - NEAT (non-exercise activity thermogenesis) - ET (exercise thermogenesis) The global obesity epidemic: increased energy intake or decreased energy expenditure ?

39 Leptin in human obesity -Circulating leptin levels are regulated by fat mass, gender, fed-fasted state. -Although loss-of-function mutations in the leptin or leptin-receptor genes have been described, this is likely a very rare cause of human obesity. -Common human obesity is associated with elevated circulating leptin levels, which are believed to represent a state of leptin resistance.  Leptin therapy trials are largely ineffective in common human obesity

40 Leptin-induced signal transduction pathways * * * * ** (Cell Biol. Int. 28: 159, 2004) Signal termination? Leptin resistance? Overexpression of SOCS3 could be a mechanisms for leptin resistance (Nat. Med. 10: 734, 2004)

41 Copyright ©2006 BMJ Publishing Group Ltd. Druce, M et al. Arch Dis Child 2006;91: Figure 3 Summary of main gut hormones involved in appetite regulation and their sites of production. CCK, cholecystokinin; PYY, peptide YY; GLP1, glucagon-like peptide 1; GLP2, glucagon-like peptide 2.

42 Changes in GI hormones in obesity: pathophysiological relevance and potential for therapy?, 2005 Anorexigenic/ orexigenic OAAAAAOAAAAA AAAAAAAA Weight loss restores levels  role in the low rate of wieght loss maintenance? Food-induced ghrelin supression is decreased in obese  role in low satiety signal  over-eating?

43 The Incretin Glucagon-like peptide 1 (GLP-1) Lancet, 368: 1696, Secreted by L-cells in the distal illeum and colon in response to food intake. - Circulating levels rise from 5-10 pM to pM within minutes  neural input? - Levels decrease rapidly due to proteolytic cleavage by dipeptidyl peptidase 4 (DPP- 4). - Signals through distinct G- couples receptor, GLP-1R, expressed in islet α and β cells, nerves, heart, kidney.

44 Summary: GI, pancreatic and adipose signals for hypothalmic regulation of food intake

45 The endocannabinoid system in energy balance Metabolic effects of cannabis are mediated through the GPCR cannabinoid receptors (CB1 and CB2), and include : Brain: - Hypothalamus: increase orixogenic, inhibit anorexigenic signals - Mesolimbic system: increased reward and palatability of food - hindbrain: inhibition of nausea and satiety signals (Afferent Vagus) GI: - potentiation of hunger signals, inhibition of satiety, - increase nutrient absorption Fat and liver: increase lipogenesis Muscle: Impair glucose uptake A CB1 antagonist, Rimonabant, is a novel anti-obesity, anti-obesity-related morbidity drug

46 Copyright ©2006 The Endocrine Society Pagotto, U. et al. Endocr Rev 2006;27: FIG. 3. Actions of CB1 antagonists on the target organs involved in food intake and metabolic control

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48 , 2005

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50 Fuel flux regulators: pancreatic hormones: Insulin, Glucagon, Somatostatin Other counter-regulatory hormones: GH, glucocorticoides Metabolite hormones: FFA (PPAR) Energy expenditure Energy intake Food intake (calories): - lipids - Carbohydrates - proteins Basal Metabolic rate: - obligatory energy expenditure - Thermogenesis Physical activity Metabolic rate regulators: Thyroid hormones: Thyroxin Beta-adrenergic hormones: adrenalin Fat tissue hormones: leptin Metabolite hormones: FFA Food intake regulator (orexigneic, anorexigenic hormones): Fat tissue –derived hormones: Leptin, adiponectin CNS neuropeptides: NPY, MSH, ACRP, POMC GI-peptides: CCK, ghrelin, PYY Pancreatic hormones: insulin Diabetes and Obesity are by far the most prevalent edndocrine disorders, involving an increasing array of hormones involved in complex regulatory circuits. Leonardo daVinci ( ) Fernando Botero ( )

51 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE)

52 Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central)

53 Components of Total Daily Energy Expenditure (TDEE) Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central)

54 Where is heat generated? Two organs of thermogenic potential: 1.Fat tissue - Brown fat (BAT) - White fat (WAT) - “atypical brown adipocytes in WAT” 2. Skeletal muscle - UCP2 and UCP3 - Fiber type: muscle efficiency thermogenesis BATWAT Energy dissipation Multilocular, small TG droplets Energy storage: Unilocular TG droplet Multiple mitochondriaFew mitochondria UCP1Some UCP2, no UCP1 Type I fiberType II fiber Oxidative: slow twitch, low fatigue Glycolytic: fast twitch, high fatigue Multiple mitochondria High capillary density Few mitochondria SERCA2 (High efficiency Ca pump) SERCA1 (Low efficiency Ca pump)

55 Can thermogenesis be manipulated to prevent and treat obesity? Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central) voluntary Involuntary (fidgeting, restlessness) ?

56 Mechanisms of cold-induced thermogenesis in mice β 1 AR: BAT hyperplasia β 3 AR: BAT hypertrophy, Mt biogenesis

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58 Any relevance to humans? (“exercise in a pill”) 1.Adipose tissue: - some evidence for generation capacity of BAT, or “atypical BA in WAT”  human β3 Adrenergic receptor agonist? 2. Skeletal muscle: - DII is expressed in humans in skeletal muscle - participates in type I to type II fiber conversion (“resistance training in a pill”)  obesity already associated with tendency to type II > type I fiber  DII is not specific to skeletal muscle – side effects?


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