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METABOLISM © Katarína Babinská, MD, PhD, MSc., Institute of Physiology, 2016 fuel – function – end products • Food – „fuel for the body“ • GIT – brak down of the sunstances in food into simple, absorbable molecules enter metabolic reactions – in the cells = utilization of substances from food METABOLISM - chemical reactions within in the cells of the body - enzyme catalyzed reactions Two aspects of metabolism • chemical conversion of substances for tissue synthesis and operation of the body (e.g. enzymes, hormones) energy A+B C • conversion of chemical energy provided by chemical bonds of nutrients into energy utilizable in cells (ATP and other high energy bonds) and its utilization for vital functions catabolism – „energy yielding metabolism“ – breakdown of substances (e.g.fat or glycogen stores in the body) – energy (of the chemical bonds) is released in form of • chemical energy - utilized for body functions (max 27 %) • heat – maintenance of the constant body temperature – required for homeostasis and normal operation of metabolic functions anabolism – „biosynthetic metabolism“ – utilisation of the available substrates for synthesis (glycogen, structural proteins, hormones, enzymes, bone tissue, etc.) – energy consumption - both anabolism and catabolism occur continuously in changing proportion - e.g. building up the body protein (anabolism) requires energy derived in catabolic processes - depending on which processess prevail, the body is in - catabolic state (fasting) - anabolic state (food intake) Metabolic reactions enzyme – driven reactions metabolic pathways – sequence of predefined enzyme driven chemical reactions (e.g. glycolysis, Krebs cycle, Cori cycle, etc.) enzyme substance A +B substance C Energetics and metabolic rate functions of the human body – require continuous supply of energy: growth, movement, „beating“ of the heart, breathing, brain function, etc. = synthesis of tissues, hormones, muscle contraction, active membrane transport, etc. Metabolic rate - is the amount of energy utilized (released) in the body Units • Joule (J) • calorie (cal) – old, but still commonly used unit • • 1 cal = 4,18 J 1Cal = 1000 cal - matabolic rate is usually expressed in kJ/ 24 hours (1 hour, 1 min) metabolic rate in a moderately active person – approx. 8 000-10 000 kJ the metabolic rate of individual tissues and organs differs - high metabolic activity: brain, liver, skeletal muscle - low metabolic rate: fat tissue http://www.nature.com/ijo/journal/v34/n2s/fig_tab/ijo2010234f6.html The metabolic rate varies throughout the day kJ 0 4 8 12 16 20 - sleep – the lowest metabolic rate (by 10-15 % than minimum when awake) - awake/during the day – an increase in metabolic rate 24 (h) Basal metabolic rate Basal metabolic rate (BMR) - lowest metabolic rate required for the maintenance of vital body functions - metabolic rate in a person who is awake and who is in basal conditions - basal conditions: 1. the person is awake 2. physical rest - lying position 3. emotional rest – elimination of emotional excitement 4. normal body temperature (~ 36-37° C) 5. neutral temperature of the environment: 20-23 °C 6. fasting state (fats or carbohydrates for 12 hours, proteins - 18 hours) - basal conditions in real life - only just after we wake up Main factors explaining the differences in BMR 1. 2. 3. 4. Age Gender Composition and size of the body Hormones Age - increasing age - the metabolic rate decreases - the highest metabolic rate (per 1 kg of body weight) is in children – growth rate - in aging – the body composition is changed – less lean tissue, more fat Body size and composition - body surface - „larger body size – higher metabolic rate“ - the metabolic rate is directly proportional to the body surface (better than to the weight or height) This is due to thermoregulation: - larger body size → bigger heat loss (through the skin → → more heat needs to be produced for thermic homeostasis (heat is produced in metabolism) Body composition: - metabolic rate depends on the fat content in the body - fat tissue - lower metabolic rate - fat free mass (e.g. muscles) - higer metabolic rate - Gender males – higher BMR than females (approx. by 5 – 7%) - explanation: • body composition of males (vs. females) - lower body fat content (metabolically less active) - more muscles (metabolically more active) • larger body size • higher concentration of testosterone (anabolic effect) Hormones Main metabolism regulating hormones include: - thyroid hormones T3, T4 (main role in metabolism regulation) - catecholamines - growth hormone - testosterone Higher production – increased metabolic rate E.g. Stress – epinephrine – higher metabolic rate Adaptation to cold climate – higher thyroxine production – elevated BMR Adaptation to hot climate – lower thyroxine production – decreased BMR Testosterone – higher BMR in males than in females Main components of daily energy expenditure (Values for a physically active individual) Thermoregulation (6 %) Specific– dynamic effect of food (6%) Physical activity 25 – 30% Arousal Basal metabolic rate (60%) Sleeping metabolic rate Factors that increase the metabolic rate 1. physical activity - major factor that increases the metabolic rate - the increase depends on DURATION and INTENSITY of the physical activity (mild – moderate – vigorous) Activity Sitting activities (eating, computer games, studying) Standing activities - light (washing dishes, cooking) Walking slowly (a walk) Walking at normal pace Walking fast Sport – light physical activity (bowling, table tennis. etc.) Sport – medium physical activity (swimming, tennis, skating, aerobic, cycling) Sport – heavy (football, athletics, jogging, hockey) Increase of BMR 1.4 1.7 2.8 3.2 3.4 3.3 5.5 6.6 strenous exercise – dramatically increases metabolic rate - major factor contributing to the energy balance between E intake – E expenditure - physical activity allows for voluntary regulation of energy expenditure - PAL – Physical activity level - indication of a person´s physical activity by a single number is the ratio between the total daily energy expenditure and 24-hour basal metabolic rate - energy expenditure in 24 h ___________________________ PAL = basal metabolic rate -for adults, a PAL above 1.75 is considered to be compatible with a healthy lifestyle PAL Daily Activities < 1.4 Hospital patient with limited physical mobility 1.4 - 1.69 Little physical activity at work or in leisure time, e.g. office worker Lifestyle Inactive Sedentary 1.7 - 2.0 Moderate physical activity at work, e.g. in construction, or some jobs in Moderately agriculture or the leisure industry. Active Office workers who work-out e.g. in gym for an 1 h/ day. 2.0 - 2.4 Considerable physical activity at work, e.g. outdoor occupations, fitness trainers who run alongside clients. Office workers who take at least moderate exercise for two or more hours/day. > 2.4 Professional athlete or sports person Very Active Extremely Active 2. Thermogenic effect of food (specific – dynamic action of food) - a term used for an increase of metabolic rate after food ingestion = energy over BMR that is used for - digestion - absorption - transport - storage of nutrients Nutrient Increase in BMR Duration of the effect Carbohydrates + 5 –10 % 3-12 h Fats + 5 –10 % 3-12 h Proteins* +30 % 12-24 h Usual mixed diet +6% 6-12 h *stimulatory effect of some AA, also protein synthesis is an energy very demanding process 3. temperature of surrounding environment, climate - neutral temperature 20-23 °C (no extra energy expenditure for thermoregulation) - hot environment (over 23 °C) – extra energy is spent to remove the excess heat from the body - sweating - cold environment (below 20 °C) – heat is produced by increased muscle activity: higher muscle tone, shivering 4. body temperature - increase of temperature by o 1°C – increase of metabolic rate by 10 % - decrease of temperature (hypothermia) – decrease of metabolic rate 5. other factors – drugs, pregnancy, caffeine, etc. – slight increase metabolic rate Cold environment – more heat is produced by an increase in metabolic rate increase Hot environment – extra energy is spent to remove the excess heat from the body body temperature temperature of the environment Increase in body temperature by o 1°C – increase of metabolic rate by 10 % neutral temperature decrease Decrease of body temperature – decrease of metabolic rate lower higher Sources of energy and free energy - Source of energy: food/nutrients – proteins, fats, carbohydrates - energy is released from nutrients in oxidation - energy value of nutrients – amount of energy liberated by oxidation of 1 g of a nutrient in the human body (physiological free E) - physical free energy– amount of heat liberated by burning (oxidation) of 1 g of nutrients in calorimeter free energy carbohydrates fat protein (alcohol physical 17 kJ 38 kJ 23 kJ 29 kJ P,F,C physiological 17 kJ 38 kJ 17 kJ * 29 kJ) Carbohydrates and fats - fully oxidized in the body (CO2, H2O), therefore - physiological free energy = physical free energy Proteins • not completely oxidized in the body • end products of their oxidation include – H2O, CO2 and energy – also nitrogen containing substances (urea, creatinine, creatine, ammonia, etc.) P,F,C • excreted from the body by urine -their bonds contain certain amount of energy • physiological free energy of proteins < physical free energy of proteins free energy carbohydrates fat protein (alcohol physical 17 kJ 38 kJ 23 kJ 29 kJ physiological 17 kJ 38 kJ 17 kJ * 29 kJ) Energy balance E equilibrium: E intake = E expenditure - optimal for a healthy adult individual positive E balance: E intake > E expenditure - excess energy is stored - body fat (main form of stored energy – 75% of energy supplies in the body) - glycogen (1% of energy stores) - leads to weight gain (may be positive or negative for health) negative E balance: E intake < E expenditure - the energy deficit is compensated by depletion of stored forms of energy (glycogen, fat, protein) - leads to weight loss gain (may be positive or negative for health) Measurement of energy expenditure 1. calculation by formula e.g. BMR = 293 . body weight (kg) 0,75 2. determination from tables (Harris – Benedict tables) - depending onweight, height, gender, age Value A – depending on age and height Value B – depending on weight BMR = Value A + Value B 3. direct calorimetry - measurement is performed in special insulated chambers - heat released from the body is measured 4. Indirect calorimetry principle: - energy expenditure is calculated indirectly - utilization of O2 and production of CO2 is measured and based on their values BMR is calculated Rationale of the method - human metabolism is aerobic -energy is released by oxidation of substrates - oxygen consumption and metabolic rate are in direct association - oxygen cannot be accumulated in the body A/ Closed method - calculation of energy expenditure is based on measurement of the consumed O2 B/ Open method - calculation of energy expenditure is based on measurement of both the consumed O2 and produced CO2 (more accurate method) For calculation of energy expenditure we must determine: amount of produced CO2 ------------------------------------1. Respiratory quotient RQ = amount of utilized O2 carbohydrates RQ = 1 C6H12O6 + 6 O2 6 CO2 + 6 H2O fats RQ = 0,7 C12H31COOH + 23 O2 16 CO2 + 16 H2O proteins RQ = 0,8 mean value on mixed diet RQ = 0,82 2. Energy equivalent (EE) – is the amount of energy liberated while using 1 l of oxygen – value derived from RQ – can be found in a table (average 20,2 kJ/ L) – it depends on the type of oxidized fuel (differs for protein, fat, carbohydrates) – oxidation of 1 mole of different nutrients requires different quantity of O2 and CO2 production is also different Tab 8.4 Energy equivalents of 1 L of oxygen for RQ from 0.69 to 1.00 (RQ – respiratory quotient, EE – energy equivalent) RQ 0.69 0.70 0.71 0.72 0.73 0.74 0.75 0.76 EE (kJ) 19.531 19.586 19.636 19.686 19.737 19.791 19.841 19.896 RQ 0.77 0.78 0.79 0.80 0.81 0.82 0.83 0.84 EE (kJ) 19.946 19.996 20.051 20.101 20.151 20.201 20.256 20.306 RQ 0.85 0.86 0.87 0.88 0.89 0.90 0.91 0.92 EE (kJ) 20.360 20.411 20.461 20.515 20.566 20.616 20.666 20.716 RQ 0.93 0.94 0.95 0.96 0.97 0.98 0.99 1.00 EE (kJ) 20.767 20.821 20.871 20.921 20.976 21.026 21.076 21.131 Metabolic rate and physical activity Physical activity • immediate increase in energy expenditure/ metabolic rate • an immediate increase in demand for a/ fuels b/ oxygen Metabolic rate physical activity kJ resting state 0 time (min) Energy sources for the muscle in physical activity 1. Phosphagen system (ATP + PC) a/ ATP - first source of energy for the muscle contraction - stores of ATP in muscles – sufficient for 1-3 sec. b/ Phosphocreatine (PC) - cannot be utilized directly ATP creatine ADP+ P + E phosphocreatinine - serves for fast re-synthesis of ATP from ADP ATP and PC supplies for 8 – 10 s ADP+ADP Main source of energy in short-lasting intense physical activity 2. Subsequently carbohydrates and fats are utilized in a/ Anaerobic metabolism – carbohydrates only b/ Aerobic metabolism AMP+ ATP Reaction of the body to physical activity - physical activity = sudden increase of requirements for O2 - systems that help to supply O2 into the muscle are activated increase of ventilation (tidal volume and frequency) higher cardiac output per minute (frequency and stroke volume) blood re-distribution into the muscle .... - Gradual activation! - balance (i.e. needs for O2 = supply of O2) is reached in approx 3-5 minutes Oxygen supply in physical activity - due to gradual activation of systems involved in O2 supply, the O2 availability increases gradually - inbetween O2 from the stores is utilized haemoglobin - higher O2 uptake - decrease of haemoglobin oxygen saturation (venous blood) A 96% V 75 % A 96% O2 bound to myoglobin utilization of physically dissolved O2 - stores of O2 are very limited - at the beginning of exercise O2 is not supplied in quantity adequate to metabolic rate - oxygen deficit is established V 50 % Oxygen deficit - is the difference between the O2 requirements for the physical activity and O2 that is supplied - consequence: energy must be provided by anaerobic metabolism Anaerobic glycolysis - only glucose can be utilized: - glucose pyruvate lactate - fast source - less efficient 1 mol of glucose anaerobic: – 2 moles of ATP aerobic – 36 moles of ATP Steady state -achieved approx. after 3-5 minutes of exercise - O2 supplied into working muscle is adequate to metabolic requirements 3. Aerobic metabolism - utilization of glucose, fatty acids Recovery period - physical activity is finished - O2 consumption remains higher and only gradually decreases to resting values Oxygen debt -is repaid = volume of O2 consumed in recovery period above baseline consumption Excess O2 is used - to replenish the O2 supplies (haemoglobin, myoglobin, O2 dissolved in blood) - for re-conversion of lactate to glucose - to replenish the stores of ATP, PC Recovery (restoration) period -heart rate, frequency of breathing are dropping down - the restoration period is finished when preexercise heart rate and breathing frequency is reestablished Maximal oxygen consumption (maximal aerobic capacity) -VO2max - is the maximum capacity of an individual's body to transport and use oxygen during exercise -reflects the physical fitness of the individual - expressed either in litres of oxygen per minute (l/min) or as millilitres of oxygen per kilogram of bodyweight per minute (ml/kg/min) - in physical activities with oxygen requirements exceeding VO2max part of the energy is derived in anaerobic processes if maximum aerobic capacity is exceeded in a heavy physical activity, no steady state occurs the physical activity requires anaerobic metabolism all the time replenishing of oxygen takes longer time (i.e. the restoration period is longer) Physical activities can be Dynamic activities • activities with joint movements and rhythmic muscle contractions (swimming, walking, training, house cleaning) • physical work is performed Static activities (also known as isometrics) • • • exerts muscles at high intensities without movement of the joints no force is acting on a trajectory (e.g. when carrying a weight) all the metabolized energy is transformed to heat Efficency of the physical work when an individual performs physical activity only part of the total energy expenditure is used for external work (exercise), the remainder appears as heat. Net efficiency of the physical work external work = _____________________________________________________________ net energy expenditure for the physical activity* *energy expenditure that is above resting metabolic rate Dynamic activities - average efficiency 25% = 0,25 - i.e. 25 % of the metabolized energy is utilized for performing the physical work and 75 % is transfromed to heat Static activities -efficiency 0% -all the energy released in metabolism is converted into heat Sources of energy for the human body • nutrients (derived from food or in stored form) Carbohydrates Fats Cannot be utilized directly! Proteins - chemical energy of their carbon bonds - must be converted into a form that the cells are able to utilize - high energy phosphate bonds -adenosine triphosphate (ATP) -cytidine triphosphate (CTP) -phosphocreatinine (CrP) - guanosino triphosphate (GTP,) etc. Adenosine triphosphate (ATP) - „universal energy currency“ - direct energy source for most cellular functions - present in all cells - last 2 bonds - high energy phosphate bonds ATP + H2O → ADP + Pi + energy ADP + H2O → AMP + Pi + energy Krebs cycle (citrate cycle, cycle of tricarboxylic acids) cyclic metabolic pathway crucial for energy metabolism occurs in the matrix of mitochondria exclusively in aerobic conditions sequence of chemical reactions, in which acetyl Co A is oxidized Co A is derived from – carbohydrates – fats – proteins product: CO2 and reduced forms of coenzymes NADH, FADH2 enter respiratory chain – ATP formation (oxidative phosphorylation) Digestion, absorption and metabolism of carbohydrates Carbohydrates and their digestion starch sacharose lactose polysaccharide disaccharide disacharid monosaccharides in food Oral cavity salivary a-amylase Small intestine pancreatic juice • a-amylase maltose Small intestine brush border - enterocytes glucose frucose •maltase glucose glucose •saccharase •lactase glucose fructose glucose galactose Blood Absorption of carbohydrates a/ absorption into the enterocyte glucose, galactose – Na+ cotransport fructose – facilitated diffusion -in the enterocyte conversion to glucose b/ absorption from the enterocyte into blood (passive mechanisms) - diffusion - facilitated diffusion Main metabolic pathways of carbohydrates • liver – most of the galactose and fructose is converted into glucose • glucose - the main form of carbohydrate in the human body • exclusive/preferred energy source for some tissues (brain, red blood cells) • the blood level is strictly controlled (insulin, glucagon) 1. Breakdown of carbohydrates (catabolsim, yields energy) Aerobic conditions: a/ Glycolysis: 1x glucose .... 2 x pyruvate (this step does not require oxygen) b/ pyruvate AcCoA Krebs cycle oxidative phosphorylation energy gain: 38 ATP Anaerobic conditions: Glycolysis: 1x glucose .... 2 x pyruvate lactate energy gain: 2 ATP When O2 is available again: lactate pyruvate glucose Krebs cycle .... other pathways of utilization 2. Formation and dergadation of glycogen (glycogenesis and glycogenolysis) - storage form of carbohydrates - formed only in liver – can be released into blood, available for other tissues muscles – cannot leave the muscle cells, serves only for muscle contraction 3. Conversion to fat – in excess of glucose – if glycogen stores are fully replenished 4. Gluconeogenesis – glucose formation from lactate, glucogenic aminoacids, glycerol (in liver) Regulation of carbohydrate metabolism insulin (anabolic) glucagon, thyroxine, growth hormone, epinephrine, glucocorticoids (catabolic) Digestion, absorption and metabolism of fats Fat digestion fats Stomach • gastric lipase Small intestine - pancreatic juice • pancreatic lipase - bile ( no enzymes) monoglycerides, fatty acids, glycerol Fat absorption Lymphatic vessels Blood Absorption of fats - duodenum to mid-jejunum - absorbed by diffusion into the enterocytes - resynthesis od triacylglycerides - chylomicron formation and release into blood lumen diffusion triacylglycerols cholesterol phospholipids proteins enterocyte blood diffusion 86 % 3% 9% 2% - apoproteins fatty acids with 10 or less carbons in the chain - transported directly into blood (by diffusion) fatty acids with more than 10 carbons in the chain - absorbed into lymph, transported by lymph into blood lymphatics Main metabolic pathways of fats 1. Lipolysis glycerol – glycolytic pathway fatty acids: β-oxidation in mitochondria product: AcCoA Krebs cycle oxidative phosphorylation ATP energy yield (stearic acid) 147 ATP 2. Deposition of fats – in form of TAG in adipose tissue (less in the liver) 3. Ketone bodies formation - acetoacetate, β –hydroxbutyrate, aceton - produced in reduced availability of glucose - production in the liver – utilization in the peripheral tissues - utilization in the Krebs cycle 4. Lipogenesis (fat synthesis from non-fat substrates) Fatty acids: from AcCoA glucose, some amino acids (+degraded lipids) Glycerol: from glucose Digestion, absorption and metabolism of proteins Protein digestion proteins Stomach • pepsin • chymosin Pancreatic juice (released into small intestine) •trypsin •chymotrypsin •carboxypeptidase polypeptides, peptides Small intestine (brush border of enterocytes) •aminopeptidases dipeptides, tripeptides, amino acids Blood Absorption of proteins a/from the lumen to the enterocyte 1. Na+ - cotransport 2. primary active transport - specific transporters for different AA (acidic, basic, neutral), dipeptides, tripeptides b/ form the enterocyte to blood passive mechanisms 1. 2. diffusion pinocytosis Main metabolic pathways of proteins 1. Protein synthesis - after entry into the cells - the amino acids form cellular proteins - in cells, only small amount of free amino acids is present - limited capacity of cells to form proteins (no protein stores can be formed) 2. Protein breakdown - degradation of amino acids - occurs almost entirely in the liver. - deamination of AA - removal of the amino groups (-NH2) A. resulting keto acids are oxidized to release energy. liver B. -NH2 → ammonia → urea (excretion by kidneys) 3. Conversion to carbohydrates and fats excess AA - deamination – gluconeogenesis - lipogenesis Enegy intake and energy expenditure in 24 hours Energy expenditure: continuous process Energy intake: 3-5x /day 0 4 8 12 16 20 Storage forms of energy adipose tissue 75 % of stores - glycogen (1% of stores - liver, muscles) - proteins – 24 % (waste of active tissues) - high energy bonds: ATP, phosphocreatinine, etc.. – very limited supplies - Depending on substrate availability: catabolism or anabolism prevails (fed state metabolism, fasting state metabolism) 24 (h) Principal metabolic pathways during the absorptive state (Fed state metabolism) Copyright 2009, John Wiley & Sons, Inc. Fed state metabolism • up to 4 hours after food ingestion • food is digested, metabolic fuels are absorbed and enter the circulation • regulation of metabolism is determined primarily by the influx of glucose from the gut into blood Hormonal regulation • insulin is released (in response to increased glucose level), • gucagon level drops down • epinephrine and cortisol do not play significant role in fed state metabolism Fuel utilization • plentiful supply of glucose - becomes the main fuel for the tissues • insulin stimulates – uptake od glucose by muscle - becomes the preferred fuel for the muscle – synthesis of glycogen in both liver and muscle – glucose uptake into adipose tissue for triacylglycerol synthesis – uptake of AA leading to and increased rate of protein synthesis • most of the absorbed triacylglycerols travel to adipose tissue for storage • the fatty acid and TAG synthesis in liver is increased (in response to increased glucose availability) – exported in VLDL to periphery – used as metabolic fuels in peripheral tissues – stored in adipose tissue Principal metabolic pathways during the postabsorptive state (Fasting state metabolism) Copyright 2009, John Wiley & Sons, Inc. Fasting state metabolism • begins about 4 hours after last meal • can extend to 4-5 days before entering the starvation state Hormonal regulation • detemined primarily by the disappearance of glucose from the blood signalling the end of fuel absorption from the gut • drop in insulin blood level • rise in glucagon level • fasting is stressful – epinephrine plays a role in fasting state metabolism Fuel utilization Glucagon causes stimulation of: – glycogen breakdown in the liver to release glucose into circulation – lipase in the adipose tissue resulting in release of free fatty acids – gluconeogenesis from amino acids and pyruvate Reduced level of insulin causes – reduced rate of glucose uptake by the skeletal muscle – reduced AA uptake into muscle and lower protein synthesis, so that AA are available for gluconeogenesis • tissues (other than brain and red blood cells) utilize preferentially fatty acids to spare glucose for the brain and RBC • liver - synthesis of ketones (because of a greater capacity to oxidize fatty acids then required to meet its own energy requirements) – for use as a metabolic fuel for other tissues (including brain) Humoral control of metabolism Thyroxine Epinephrine - significant effect on metabolism (increase) – delayed effect - lipolysis - glycoslysis - glycogenolysis - gluconeogenesis - lipolysis Insuline Glucagon - glycogenolysis - gluconeogenesis - glycogenesis - lipolysis - lipogenesis - glucose uptake by cells - glycogenesis - gluconeogenesis - glycogenolysis - lipogenesis, lipolysis - AA uptake by cells, - prot.synthesis Growth hormone - glucose sparing - uptake by muscles - lipolysis - protein synthesis in muscles Cortisol - gluconeogenesis - uptake of glucose, fatty acids and amino acids - lipolysis - protein breakdown