2. The first law of thermodynamics:
what does it say to us?
U = W + Q = work + heat
less utilizable
form of energy
2
3. Transformation of energy in human body
energy input energy output
chemical energy of nutrients = work + heat
energy of nutrients = BM + phys. activity + reserves + heat
any work requires ATP
3
4. Energy transformations in the human body are
accompanied with continuous production of heat
1 2 3
chemical proton
NADH+H+
energy
of nutrients FADH2
gradient
across IMM
ATP
heat heat heat 4
1 .. metabolic dehydrogenations with NAD+ and FAD work
2 .. respiratory chain (oxidation of reduced cofactors + reduction of O2 to H2O)
3 .. oxidative phosphorylation, IMM inner mitochondrial membrane
4 .. transformation of chemical energy of ATP into work + some heat
.. high energy systems 4
5. Two ways of ATP formation in body
95 % ATP is produced by oxidative phosphorylation (O2 needed):
ADP + Pi + energy of H+gradient ATP
5 % ATP is made by substrate-level phosphorylation:
ADP + macroergic phosphate-P* ATP + second product
* 1,3-bisphosphoglycerate (glycolysis)
phosphoenolpyruvate (glycolysis)
succinyl-CoA + Pi succinyl-phosphate (citrate cycle)
5
6. Energy data of nutrients
Nutrient Energy (kJ/g) Thermogenesis
Lipids 38 4%
Saccharides 17 6%
Proteins 17 30 %
Thermogenesis is the heat production 3-5 h after meal.
It is expressed in % of the nutrient energy ingested. Thermogenesis is the
consequence of digestion, absorption, and metabolism of nutrient.
6
7. Basal metabolism (BM) can be estimated from
body mass: 0.1 MJ / kg / day
body surface: 4.2 MJ / m 2 / day
Example: 70 kg BM = 0.1 × 70 = 7 MJ/day
7
8. Basal metabolism depends on some factors
• Gender (in females by 10 % lower)
• Age (with increasing age BM decreases)
• Body temperature
(increasing temperature by 1 C increases BM by 12 %)
• environmental temperature – increased in cold climates
• Hormones thyroxine and adrenaline - increase BM
• Long starvation – BM decreases
8
11. Energy reserves in the adult body (male, 70 kg)
Compound Tissue Mass (g) Energy (MJ)
Glycogen liver 70 1,2
Glycogen muscles 120 2,0
Glucose ECF 20 0,3
Lipids adipose t. 15 000 570
Proteins muscles 6 000 102/3 = 34
• the biggest energy store is in adipose tissue
• total body fat makes 10-30 % (males , females )
• only ⅓ of muscle proteins can be used as fuel
• liver glycogen lasts approx. 24 h
• muscle glycogen – can be utilized only in muscles (lack of glucose 6-phosphatase)
11
12. Basic facts on metabolism
• ATP is universal source of chemical energy
• ATP is produced in the catabolism of nutrients
• there are two ways how to produce ATP (see page 5)
• body needs the constant level of ATP and glucose
• Glucose is prominent metabolic fuel for brain and erythrocytes
• glucose is also needed to utilize energy from lipids
= for citrate cycle (Glc pyruvate oxaloacetate CAC)
• glucose cannot be produced from lipids
12
13. Metabolic intermediates and their relations
TAG
glucose
glukosa glycerol
MK
FA
irreversible
nevratná irreversible
nevratná ketogenic AA
pyruvát
pyruvate acetyl-CoA ketogenní AK
mixed AA
- CO2
essential
glukogenní AK
glucogenic AA CC
13
14. Interconversions between nutrients
Interconversion Commentary
Sugars lipids very easy and quickly
not possible,
Lipids glucose
× pyruvate dehydrogenase reaction is irreversible
Amino acids glucose most AA are glucogenic
pyruvate and CAC intermediate provide carbon
Glucose intermediates AA
skeleton for some amino acids
Amino acids lipids in excess of proteins
pyruvate dehydrogenase reaction is irreversible
×
Lipids amino acids
ketogenic AA and most mixed AA are essential
14
15. Metabolism in resorption phase
• after substantial meal
• all nutrients available in sufficient amounts
• chemical energy is stored (glycogen, lipids)
• principal hormonal regulation - insulin
15
16. Saccharides after meal (insulin)
ery
liver CO2 brain
lactate
glycogen
NADPH
Glc high blood Glc
muscle
glycogen
TAG CO2
Gln
Glc CO CO2
glycerol-P CO2
2
GIT TAG
adipose
GLUT 4 insulin dependent transporter 16
17. Glucose (Glc) in liver after meal
• Glc glycogen
• Glc pyruvate acetyl-CoA CAC energy
• Glc pyruvate acetyl-CoA FA TAG (VLDL)
• considerable amount of Glc just passes through liver into blood
• small portion of Glc is converted into specialized products
(pentoses + NADPH, galactose, glucuronate)
• excess of Glc lipids (VLDL) blood adipose tissue
obesity
17
18. Glucose in extrahepatic tissues after meal
• Glc is the only fuel for erythrocytes (anaerobic glycolysis)
• Glc is prominent fuel for brain (aerobic glycolysis)
• Glc is source of energy in (resting) muscles (aerobic glycolysis)
+ substrate for muscle glycogen (limited capacity)
• Glc is source of energy, glycerol-3-P, and NADPH+H+ (pentose cycle)
for TAG synthesis in adipose tissue
Glc glyceraldehyde-3-P + dihydroxyacetone-P
glycerol-3-P
18
19. Lipids and proteins after meal (insulin)
BCAA
liver
Glc
proteins blood plasma
proteins
FA
LPL
AA TAG FA
VLDL muscle
NH3
CO2
LPL
AA TAG
FA + glycerol-P
chylomicrons
Gln LPL FA
intestine
TAG
adipose tissue myocardium
19
20. Lipids after meal
• Exogen. TAG (CM) and endogen. lipids (VLDL) supply mainly
adipose, less other tissues (muscles, myocard, kidney)
• FA are released from TAG by the action of LPL
• In adipose, FA are substrates for TAG synthesis
• LPL is activated by insulin mainly in adip. t. (not very in
muscles) – exog. lipids (CM) are directed to adipose tissue
• FA are secondary fuel for muscles (primary = glucose)
FA acetyl-CoA CAC CO2 + energy
20
21. Amino acids after meal
• AA are partially metabolized in enterocytes (Gln)
• some AA are utilized in liver (proteosynthesis)
• AA excess synthesis of FA and TAG
• Val, Leu, Ile (BCAA) are not utilized in liver (lacking
aminotransferases), they are directed to muscles and brain
21
22. Organ functions in absorptive state (insulin)
• increased glucose phosphorylation Glc-6-P (glukokinase)
• Glc-6-P CO2 + energy (metabolic fuel for liver – quite exceptionally !!)
• Glc-6-P glycogen (glucose stores for other tissues)
Liver
• Glc-6-P NADPH+H+ (pentose cycle) FA TAG VLDL
• AA hepatic + blood plasma proteins
• AA surplus carbon skeleton + ammonia urea
• increased glucose influx (GLUT4 / insulin)
• increased glycolysis energy + glycerol-3-P (for lipogenesis)
Adipose
• increased pentose cycle FA (FA synthesis de novo is not relevant)
• influx of FA (CM + VLDL / LPL) TAG (lipogenesis)
• increased glucose influx (GLUT4 / insulin)
• glucose CO2 + energy
Muscle
• increased glycogen synthesis (for itself only)
• uptake of AA (esp. BCAA) protein synthesis (+ AA oxidation)
Brain • glucose CO2 + energy
Kidney • glucose / FA / glutamine CO2 + energy
22
23. Insulin
• After meal, insulin is released from β-cells of pancreas
• 2. messenger ??
• decreases blood glucose by four processes:
A) supports glucose entry into muscles and adipocytes
B) stimulates glycogen synthesis (liver, muscles)
C) inhibits liver glycogenolysis + gluconeogenesis
D) supports glycolysis in liver, muscles, and other tissues
• stimulates TAG synthesis (adipocytes, liver) and proteosynthesis
(muscles)
23
24. Insulin is anabolic hormone
Stimulates the synthesis of energy stores and cellular utilization of glucose
fatty acids TAG
CO2 glycolysis
glucose glycogen
amino acids proteins
Insulin induces the synthesis of key enzymes of glycolysis (glucokinase,
phosphofructokinase, pyruvate kinase) a glycogenesis (glycogen synthase)
24
25. Post-resorption phase
• in fasting (first feelings of hunger)
• about 10-12 h after meal (morning before breakfast)
• Hormonal influence - glucagon
25
26. Saccharides and proteins in fasting (glucagon)
ery
liver CO2 brain
glycogen lactate
(100%)
phosphorolysis muscle
glycogen
Glc Glc in blood
CO2
90% gluconeogenesis
lactate
Ala, Gln
proteolysis
10% gluconeogenesis
Gln CO2
kidney
GIT metabolic fuel for 26
some tissues
27. Glucose in fasting (glucagon)
blood Glc level is maintained by two processes:
• (1) liver glycogenolysis (phosphorolysis)
(Glc)n + Pi (Glc)n-1 + Glc-1-P phosphorylase is activated
by glucagon (and adrenaline)
Glc-6-P free glucose
• (2) liver gluconeogenesis from
alanine, lactate, glycerol .... recycling three C atoms (saving Glc)
other glucogenic AA glucagon induces the synthesis of three key enzymes:
phosphoenolpyruvate carboxykinase (PEPCK)
fructose-1,6-bisphosphatase
glucose-6 phosphatase
27
28. Most amino acids (14) are glucogenic
Ser, Gly, Thr, Ala, Cys, Trp
Ala, Cys, Gly, Ser, Thr, (Trp)
pyruvát
pyruvate
glucose
glukosa
Ile, Leu, Lys, Thr
acetyl-CoA acetoacetate
acetoacetát
Leu, Lys, Phe, Trp, Tyr
oxalacetát
Asp, Asn oxaloacetate
CC 2-oxoglutarát
2-oxoglutarate Arg, Glu, Gln, His, Pro
Phe, Tyr fumarát
fumarate
Asp
succinyl-CoA
sukcinyl-CoA
Ile, Val, Met, Thr
28
29. Lipids in fasting (glucagon)
CO2
liver brain
muscle
ketone bodies KB in blood
CO2
Acetyl-CoA
FA FA-albumin
CO2
FA + glycerol
HSL kidney
Gln CO2
TAG myocardium
GIT adipocyte 29
30. Lipids in post-resorption phase
• lipolysis in adipocytes
• hormon sensitive lipase (HSL) is activated by glucagon
• FA transported in ECF in complex with albumin
• FA are fuel for liver, muscles, heart and other tissues
• ketone bodies utilized in muscles, partially in CNS
30
31. Glucagon is antagonist of insulin
• 2. messenger is cAMP
• stimulates the degradation of energy stores:
glycogen (liver), TAG (adipocyte), proteins (liver)
• supports gluconeogenesis from lactate and AA
• inhibits synthesis of glycogen, TAG, and proteins
• acts on liver and adipocytes (not muscles)
31
32. Glucagon is antagonist of insulin
(ketogenic hormone)
CO2 fatty acids TAG
glucose glycogen
ketone
bodies
amino acids
32
33. Ketone bodies
OH O O O
- 2H O
H3C CH CH2 C H3C C CH2 C H3C C CH3
- CO
OH + 2H O H 2
-hydroxymáselná kyselina
β-hydroxybutyrate acetoacetate
acetoctová kyselina acetone
aceton
anion anion non–electrolyte
Cl-
Na+
HCO3-
OA
K+
33
34. KB as metabolic fuel
succinyl-CoA: acetoacetate-CoA transferase
O O O
H3C C CH2 COOH H3C C CH2 C acetoacetyl-CoA
acetoacetát
acetoacetate SCoA
succinyl-CoA
sukcinyl-CoA sukcinát
succinate
S CoA
H
O CAC
CC
2 H3C C Energie
energy
SCoA
34
35. Organ functions in fasting state (glucagon)
• increased glycogen degradation (glycogenolysis)
glucose 6-phosphatase
Liver • gluconeogenesis (from Ala, AA, lactate/pyruvate, glycerol)
• increased FA oxidation acetyl-CoA KB export of KB
• increased lipolysis (HSL / glucagon, adrenaline) FA + glycerol
Adipose
• increased release of FA into blood
• FA (from adipose) + KB (from liver) CO2 + energy
Muscle • in longer fasting only FA are oxidized
• proteolysis AA (esp. Ala, Gln – for liver gluconeogenesis) / cortisol
• glucose CO2 + energy
Brain
• KB CO2 + energy (in longer fasting)
• glucose / FA / KB / glutamine CO2 + energy
Kidney • gluconeogenesis (for itself and other)
• compensate ketoacidosis: Gln/Glu NH3 + H+ NH4+ (release into urine)
35
36. Metabolic turn-over of saccharides in fasting (g/d)
liver CNS
Early fasting
144
glycogen
Proteins AA 75
Glc
gluconeogenesis 180 Ery
glycerol 36
16 lactate
36
Prolonged starvation liver CNS
44
Proteins AA 20
Glc
gluconeogenesis 80 Ery
glycerol 36
15 lactate
50 36
37. Metabolic turn-over of saccharides in fasting/starvation
• liver gluconeogenesis gradually decreases
• muscle proteolysis gradually decreases
• substrates for gluconeogenesis remain the same
(lactate, amino acids, glycerol)
• CNS utilization of glucose decreases
• erythrocytes consume constantly the same amount
of Glc (36 g/d) – it can make up to 45 % from Glc production
37
38. Metabolic turn-over of lipids in fasting (g/d)
Early fasting liver
gluconeogenesis
glycerol KB
FA 60
40
adip. t.
TAG 160 FA FA muscles, myocard, kidney
160 120
liver
Prolonged starvation CNS
47
gluconeogenesis
glycerol KB
FA 57
38 x
adip. t.
TAG 150 FA FA muscles, myocard, kidney
150 112 38
10
urine
39. Metabolic turn-over of lipids in fasting/starvation
• the extent of lipolysis is approximately the same
• the production of KB is approximately the same acidosis
• muscles stop utilizing ketone bodies
• the brain gradually adapts for KB
39
40. Two main priorities in starvation
• saving glucose (utilization of KB in brain)
• saving proteins (= KB save gluconeogenesis from AA)
40
41. Metabolism in stress - catecholamines
• noradrenaline, adrenaline – released from adrenal medulla
• act through adrenergic receptors
• β-receptors: cAMP (muscles, adipocytes)
• α1-receptors: DAG + IP3 / Ca2+ (liver)
• very quick action (seconds)
• catecholamines stimulate mainly:
• glycogenolysis in liver ( increase of blood Glc)
• glycogenolysis and glycolysis in muscles
• lipolysis in adipose tissues
• energy supply for muscles – they must quickly respond to
stress situation (fight, flight)
41
42. Metabolism in the fight or flight situation
adrenaline
liver
glycogen
Glc muscles glycogen
adipocyte ATP
Glc
TAG FA
42
43. Glucocorticoids are released in chronic stress
• cortisol prepares the body for adrenaline action
• regulates gene expression – slow effect – hour to days
• stimulates the synthesis of HSL in adipocytes – at the moment of
stress there is enough enzyme available to perform lipolysis
• support muscle proteolysis – substrates for gluconeogenesis
• induces synthesis of PEPCK (gluconeogenesis) and glycogen synthase
43
44. Fat reserves in adult body
Feature Males Females
Total body water 60 – 67 % 50 - 55 %
Total body fat 10 – 20 % 20 – 30 %
waist, abdomen hips, thighs
Main fat distribution
android type, apple-shaped gynoid type, pear-shaped
Subcutaneous and visceral fat
80 – 90 % fat is stored in subcutaneous depots
10 – 20 % is visceral (omental, mesenteric) fat – close to portal vein, free FA and
proinflammatory cytokines from visceral fat go directly to liver – increased
synthesis of VLDL – increased health risk (obesity and other diseases)
44
46. Selected adipokines
produced in adipocytes in proportion to fat mass, acts in hypothalamus as
Leptin the signal of satiation, in obesity - decreased hypothalamus response to
leptin
produced in adipocytes, improves tissue sensitivity to insulin,
Adiponectin
in obesity and DM II – decreased production of adiponectin
produced by macrophages, decreases tissue sensitivity to insulin,
Resistin
in obesity – increased level
Visfatin produced by visceral fat tissue, improves tissue sensitivity to insulin
macrophage chemoattractant protein, produced in adipocytes and other
MCP
cells, attracts macrophages into hypertrophic adipocytes
tumor necrosis factor, produced by macrophages, pro-inflammatory
TNF-α effects, decreases tissue sensitivity to insulin, stimulates lipolysis
(paracrine effect)
46
47. Metabolism in obesity
• higher intake of energy than expenditure increased size (hypertrophy) and
number (hyperplasia) of (pre)adipocytes, mainly in abdominal region
• after certain adipocyte size – lipolysis elevated plasma FA
• adiponectin production decreases
• hypothalamus becomes less sensitive to leptin
• increased production of MCP + TNF-α pro-inflammatory effects insulin
resistance atherosclerosis metabolic syndrome
• hypertrophic adipocytes have insufficient oxygen supply, lose ability to store
fat, just opposite – release FA
• TAG are stored in other organs: muscles, heart, pancreas, liver (steatosis) with
many pathological consequencies
47
48. mass (kg)
Body mass index BMI
[height (m)]2
BMI Classification
< 18,5 underweight
18,5 - 24,9 normal weight
25,0 - 29,9 overweight
30,0 – 34,9 obesity class I
35,0 – 39,9 obesity class II
> 40 obesity class III (extreme)
48
49. Criteria of obesity
• BMI, obesity if > 30 (males), > 28.6 (females)
• WHR (waist hip ratio)
normal values: < 0,95 (males), < 0,85 (females)
• waist circumference,
normal values: < 94 cm (males), < 84 cm (females)
• other instrumental methods: bioelectrical impedance analysis
49
