1. מאזן האנרגיה וההוצאה האנרגטית - הבסיס לטיפול בשינויי אורח חיים
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

2. בקרת משקל הגוף: פשוט מאוד....
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 expenditure
Energy intake

4. The energy balance: Energy expenditure Energy intake 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. orexigenic =
= anorexigenic
Hypothalamus

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

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

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

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

14. The energy balance: Energy expenditure Energy intake 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)

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

16. Facultative (adaptive) thermogenesis Obligatory thermogenesis
Components of Total Daily Energy Expenditure (TDEE)
Facultative (adaptive) thermogenesis
30%
(20 to >100)
Exercise 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
none
6-12 %
Essential thermo.
Endothermic thermo.
Diet-induced thermogenesis
Obligatory thermogenesis
~ 60%

17. 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!!

18. נוראדרנלין והורמון הטירואיד מבקרים את המספר והיעילות האנרגטית של מיטוכונדריות
Noradrenalin
Thyroid hormone
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
mitochondria
mtTF-A

19. The energy balance צריכת האנרגייה מבקרת את ההוצאה האנרגטית
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
Body mass
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

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)
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)

24. The coupling, uncoupling, and futile cycling of reactions in energy metabolism:
Fuel combustion
ATP synthesis
ATP utilization for work
פוטנציאל
אלקטרו-כימי
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
חומר מחזר

25. Coupling the electron transport chain to ATP synthesis
NADH + H+ + ½O NAD+ + H2O DG = kCal/mol 3ADP +3Pi ATP DG = 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
Energy
+ADP +Pi
Food
Combustion
ATP
+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
Food composition choices:
High protein? Low carb? (Increase satiety?)
Decreasing energy extraction from food – dairy products?
Decrease highly calorie-dense foods
Decrease soft drinks
Increasing NEAT:
life style choices
work environment engineering
cultural change
GI microbial flora:
Decreasing energy extraction from food (Nature 444: 1027, 2006)
Increasing DIT:
Low quality protein?

30. משמעויות טיפוליות – פרמקולוגיה
Energy expenditure
Energy intake
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)

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
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
Increasing NEAT:
life style choices
work environment engineering
cultural change
Increasing DIT:
Low quality protein?

32. Thank you !
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:
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)  FADH2 (Mt)  2ATP
NADH (cytosol)  NADH (Mt)  3ATP

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

38. Obesity: energy imbalance
Energy intake
Energy expenditure
The global obesity epidemic:
increased energy intake or decreased 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

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

41. 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.
Druce, M et al. Arch Dis Child 2006;91:
Copyright ©2006 BMJ Publishing Group Ltd.

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

43. The Incretin Glucagon-like peptide 1 (GLP-1)
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.
Lancet, 368: 1696, 2006

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. FIG. 3. Actions of CB1 antagonists on the target organs involved in food intake and metabolic control
Pagotto, U. et al. Endocr Rev 2006;27:73-100
Copyright ©2006 The Endocrine Society

48. , 2005

49. , 2005

50. Energy expenditure
Energy intake
Basal Metabolic rate:
- obligatory energy expenditure
Thermogenesis
Physical activity
Food intake (calories):
lipids
Carbohydrates
proteins
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
( )
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
Fuel flux regulators:
pancreatic hormones: Insulin, Glucagon, Somatostatin
Other counter-regulatory hormones:
GH, glucocorticoides
Metabolite hormones: FFA (PPAR)
Metabolic rate regulators:
Thyroid hormones: Thyroxin
Beta-adrenergic hormones:
adrenalin
Fat tissue hormones: leptin
Metabolite hormones: FFA

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

52. Facultative (adaptive) thermogenesis Obligatory thermogenesis
Components of Total Daily Energy Expenditure (TDEE)
Exercise thermogenesis
Essential thermo.
Endothermic thermo.
Diet-induced thermogenesis
Muscle efficiency thermo
Cold-induced shivering thermo
Cold-induced non-shivering thermo
Facultative (adaptive) thermogenesis
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)
Obligatory thermogenesis

53. Facultative (adaptive) thermogenesis Obligatory thermogenesis
Components of Total Daily Energy Expenditure (TDEE)
Exercise thermogenesis
Essential thermo.
Endothermic thermo.
Diet-induced thermogenesis
Muscle efficiency thermo
Cold-induced shivering thermo
Cold-induced non-shivering thermo
Facultative (adaptive) thermogenesis
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)
Obligatory thermogenesis

54. Where is heat generated? Two organs of thermogenic potential:
Fat tissue
- Brown fat (BAT)
- White fat (WAT)
- “atypical brown adipocytes in WAT”
2. Skeletal muscle
- UCP2 and UCP3
- Fiber type: muscle efficiency thermogenesis
BAT
WAT
Energy dissipation
Multilocular, small TG droplets
Energy storage:
Unilocular TG droplet
Multiple mitochondria
Few mitochondria
UCP1
Some UCP2, no UCP1
Type I fiber
Type 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. Facultative (adaptive) thermogenesis Obligatory thermogenesis
Can thermogenesis be manipulated to prevent and treat obesity?
Exercise thermogenesis
Essential thermo.
Endothermic thermo.
Diet-induced thermogenesis
Muscle efficiency thermo
Cold-induced shivering thermo
Cold-induced non-shivering thermo
Facultative (adaptive) thermogenesis
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) ?
Obligatory thermogenesis

56. Mechanisms of cold-induced thermogenesis in mice
β1AR: BAT hyperplasia
β3AR: BAT hypertrophy, Mt biogenesis

58. Any relevance to humans? (“exercise in a pill”)
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?