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Integration of metabolism

Biochemický ústav LF MU (J.D.) 2011

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The first law of thermodynamics:

what does it say to us?

U = W + Q = work + heat

less utilizable

form of energy

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Transformation of energy in human body

chemical energy of nutrients = work + heat

energy of nutrients = BM + phys. activity + reserves + heat

energy input energy output

any work requires ATP

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chemicalenergy

of nutrients

heat

NADH+H+

FADH2

protongradient

across IMM

heat heat

ATP1 2 3

1 .. metabolic dehydrogenations with NAD+ and FAD

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

Energy transformations in the human body are

accompanied with continuous production of heat

work

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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)

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Nutrient Energy (kJ/g) Thermogenesis

Lipids 38 4 %

Saccharides 17 6 %

Proteins 17 30 %

Energy data of nutrients

Thermogenesis is the heat production 3-5 h after meal.It is expressed in % of the nutrient energy ingested. Thermogenesis is theconsequence of digestion, absorption, and metabolism of nutrient.

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Basal metabolism (BM) can be estimated from

body surface: 4.2 MJ / m2 / day

body mass: 0.1 MJ / kg / day

Example: 70 kg BM = 0.1 × 70 = 7 MJ/day

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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

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Recommended intake of nutrients

Nutrient Percentage of energy intake/day

Starch

Lipids

Proteins

55 - 60 %

30 %

10 - 15 %

SAFA 5 %

MUFA 20 %

PUFA 5 %

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The content of nutrients in foods

Saccharides Lipids Proteins

Table sugar (100 %) Plant oils (100 %) Parmesan cheese (40 %)

Rice (80 %) Kitchen fat (100 %) Emmental cheese (30 %)

Bread roll (60 %) Butter (80 %) Turkey steak (20 %)

Bread (50 %) Margarins (60-80 %) Carp (16 %)

Potatoes (15 %) Fatty meat (20-40 %) Bread (10 %)

Milk (5 %) Milk (3 %) Milk (4 %)

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Energy reserves in the adult body (male, 70 kg)

Compound Tissue Mass (g) Energy (MJ)

Glycogen

Glycogen

Glucose

Lipids

Proteins

liver

muscles

ECF

adipose t.

muscles

70

120

20

15 000

6 000

1,2

2,0

0,3

570

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)

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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

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Metabolic intermediates and their relations

pyruvát

glukosa

acetyl-CoAnevratná nevratná

ketogenní AK

CCglukogenní AK

MK

glycerolTAG

- CO2

essential

FA

glucose

pyruvate

glucogenic AA

ketogenic AAmixed AA

irreversibleirreversible

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Interconversions between nutrients

Interconversion Commentary

Sugars lipids very easy and quickly

Lipids glucosenot possible,pyruvate dehydrogenase reaction is irreversible

Amino acids glucose most AA are glucogenic

Glucose intermediates AApyruvate and CAC intermediate provide carbonskeleton for some amino acids

Amino acids lipids in excess of proteins

Lipids amino acidspyruvate dehydrogenase reaction is irreversible

ketogenic AA and most mixed AA are essential

×

×

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Metabolism in resorption phase

• after substantial meal

• all nutrients available in sufficient amounts

• chemical energy is stored (glycogen, lipids)

• principal hormonal regulation - insulin

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Saccharides after meal (insulin)

Glc

GIT

liver

Glc

glycogen

high blood Glc

lactate

ery

brainCO2

TAG

NADPH

adipose

glycerol-P

TAG

muscle

glycogen

CO2

GLUT 4 insulin dependent transporter

Gln

CO2

CO2

CO2

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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

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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

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AA

intestine

liverGlc

TAG

adipose tissue

FA + glycerol-P

TAG

muscle

CO2

AA

TAG

VLDL

FA

myocardium

FA

chylomicrons

LPL

LPL

LPL

proteins

Gln

Lipids and proteins after meal (insulin)

blood plasmaproteins

NH3

BCAA

FA

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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

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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

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Organ functions in absorptive state (insulin)

Liver

• 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)

• Glc-6-P NADPH+H+ (pentose cycle) FA TAG VLDL

• AA hepatic + blood plasma proteins

• AA surplus carbon skeleton + ammonia urea

Adipose

• increased glucose influx (GLUT4 / insulin)

• increased glycolysis energy + glycerol-3-P (for lipogenesis)

• increased pentose cycle FA (FA synthesis de novo is not relevant)

• influx of FA (CM + VLDL / LPL) TAG (lipogenesis)

Muscle

• increased glucose influx (GLUT4 / insulin)

• glucose CO2 + energy

• 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

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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)

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Insulin is anabolic hormone

fatty acids TAG

glucose glycogenCO2glycolysis

amino acids proteins

Stimulates the synthesis of energy stores and cellular utilization of glucose

Insulin induces the synthesis of key enzymes of glycolysis (glucokinase,

phosphofructokinase, pyruvate kinase) a glycogenesis (glycogen synthase)

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Post-resorption phase

• in fasting (first feelings of hunger)

• about 10-12 h after meal (morning before breakfast)

• Hormonal influence - glucagon

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Saccharides and proteins in fasting (glucagon)

GIT

liver

Glc

glycogen

Glc in blood

lactate(100%)

ery

brainCO2

muscle

glycogen

90% gluconeogenesis

10% gluconeogenesis

kidney

lactate

CO2

proteolysisAla, Gln

Gln CO2

phosphorolysis

metabolic fuel forsome tissues

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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

Glc-6-P free glucose

• (2) liver gluconeogenesis from

alanine, lactate, glycerol .... recycling three C atoms (saving Glc)

other glucogenic AA

phosphorylase is activatedby glucagon (and adrenaline)

glucagon induces the synthesis of three key enzymes:

phosphoenolpyruvate carboxykinase (PEPCK)

fructose-1,6-bisphosphatase

glucose-6 phosphatase

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oxalacetát

fumarát

sukcinyl-CoA

2-oxoglutarát

CC

acetyl-CoA

Phe, Tyr

Ile, Val, Met, Thr

Arg, Glu, Gln, His, Pro

Asp, Asn

glukosa

acetoacetát

pyruvát

Ala, Cys, Gly, Ser, Thr, (Trp)

Ile, Leu, Lys, Thr

Leu, Lys, Phe, Trp, Tyr

Asp

Ser, Gly, Thr, Ala, Cys, Trp

Most amino acids (14) are glucogenic

pyruvateglucose

fumarate

succinyl-CoA

2-oxoglutarate

oxaloacetate

acetoacetate

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Lipids in fasting (glucagon)

GIT

liver

Acetyl-CoA

ketone bodies KB in blood

brain

CO2

muscle

FA

CO2

adipocyte

FA + glycerol

TAG

FA-albumin

myocardium

kidneyHSL

CO2

Gln CO2

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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

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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)

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Glucagon is antagonist of insulin(ketogenic hormone)

fatty acids TAG

glucose glycogen

CO2

amino acids

ketonebodies

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Ketone bodies

H3C C CH3

O

H3C CH CH2 C

O

OH

OH

H3C C CH2

O

C

O

O H- CO2

- 2H

+ 2H

-hydroxymáselná kyselina acetoctová kyselina aceton

non–electrolyte

β-hydroxybutyrate acetoacetate acetone

anion anion

Na+

Cl-

HCO3-

OAK+

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KB as metabolic fuel

H3C C CH2

O

COOH

sukcinyl-CoA sukcinát

H3C C CH2

O

C

SCoA

O

S

H

CoA

C

SCoA

O

H3C2

CCEnergie

acetoacetát

acetoacetyl-CoA

energyCAC

acetoacetate

succinate

succinyl-CoA: acetoacetate-CoA transferase

succinyl-CoA

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Organ functions in fasting state (glucagon)

Liver

• increased glycogen degradation (glycogenolysis)

• gluconeogenesis (from Ala, AA, lactate/pyruvate, glycerol)

• increased FA oxidation acetyl-CoA KB export of KB

Adipose• increased lipolysis (HSL / glucagon, adrenaline) FA + glycerol

• increased release of FA into blood

Muscle

• FA (from adipose) + KB (from liver) CO2 + energy

• in longer fasting only FA are oxidized

• proteolysis AA (esp. Ala, Gln – for liver gluconeogenesis) / cortisol

Brain• glucose CO2 + energy

• KB CO2 + energy (in longer fasting)

Kidney

• glucose / FA / KB / glutamine CO2 + energy

• gluconeogenesis (for itself and other)

• compensate ketoacidosis: Gln/Glu NH3 + H+ NH4+ (release into urine)

glucose 6-phosphatase

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Metabolic turn-over of saccharides in fasting (g/d)

glycogen

gluconeogenesis

liver

Proteins AA

glycerol16

144

CNS

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Ery

lactate

36

Glc180

gluconeogenesis

liver

glycerol15

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CNS

36

Ery

lactate

50

Glc80

Early fasting

Prolonged starvation

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20Proteins AA

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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

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Metabolic turn-over of lipids in fasting (g/d)

gluconeogenesis

liver

glycerol KB

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Early fasting

Prolonged starvation

TAG 160

FA40

FA160

FA120

muscles, myocard, kidney

gluconeogenesis

liver

glycerol KB

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TAG 150

FA38

FA150

FA112

muscles, myocard, kidney

10urine

CNS

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x

adip. t.

adip. t.

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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

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Two main priorities in starvation

• saving glucose (utilization of KB in brain)

• saving proteins (= KB save gluconeogenesis from AA)

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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 tostress situation (fight, flight)

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Metabolism in the fight or flight situation

liver

FA

muscles

adrenaline

TAG

glycogen

glycogenGlc

Glcadipocyte ATP

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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

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Fat reserves in adult body

Feature Males Females

Total body water 60 – 67 % 50 - 55 %

Total body fat 10 – 20 % 20 – 30 %

Main fat distributionwaist, abdomenandroid type, apple-shaped

hips, thighsgynoid 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 andproinflammatory cytokines from visceral fat go directly to liver – increasedsynthesis of VLDL – increased health risk (obesity and other diseases)

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Selected adipokines

Leptinproduced in adipocytes in proportion to fat mass, acts in hypothalamus asthe signal of satiation, in obesity - decreased hypothalamus response toleptin

Adiponectinproduced in adipocytes, improves tissue sensitivity to insulin,in obesity and DM II – decreased production of adiponectin

Resistinproduced by macrophages, decreases tissue sensitivity to insulin,in obesity – increased level

Visfatin produced by visceral fat tissue, improves tissue sensitivity to insulin

MCPmacrophage chemoattractant protein, produced in adipocytes and othercells, attracts macrophages into hypertrophic adipocytes

TNF-αtumor necrosis factor, produced by macrophages, pro-inflammatoryeffects, decreases tissue sensitivity to insulin, stimulates lipolysis(paracrine effect)

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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

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Body mass index 2(m)][height

(kg)massBMI

BMI Classification

< 18,5

18,5 - 24,9

25,0 - 29,9

30,0 – 34,9

35,0 – 39,9

> 40

underweight

normal weight

overweight

obesity class I

obesity class II

obesity class III (extreme)

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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