Metabolism
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Summary - why do we need to eat and how do we survive between meals?
Key points from this exercise:
Even at rest there is some work being performed by muscles - to maintain circulation and breathing and generally maintain muscle tone.
Sodium, potassium and calcium ions are transported across cell membranes and between intracellular compartments by active transport, which is energy requiring.
There is continual breakdown of tissue proteins and replacement synthesis - both processes are energy requiring.
Many enzyme catalysed reactions are endothermic and require an input of energy.
BMR is the energy expenditure by the body when completely at rest, but awake, at a comfortable temperature and about 4 hours after a meal.
The "gold standard" method is to measure heat output from the body in an insulated room that is maintained at a constant temperature by passing cold water through pipes and measuring the increase in temperature of the water. It is also possible to measure the energy expenditure in a limited number of activities (and for a limited time) in the same way.
More usually, BMR and energy expenditure in physical activity are measured by measuring oxygen consumption. To first approximation there is an energy expenditure of 20 kJ for each litre of oxygen consumed.
The ratio of carbon dioxide formed : oxygen consumed (the Respiratory Quotient, RQ) differs for oxidation of fat, carbohydrate and protein. An RQ near to 1 indicates that mainly carbohydrate is being oxidised, and RQ near 0.7 indicates that mainly fat is being oxidised. Measurement of urinary excretion of urea permits estimation of the amount of amino acids being oxidised.
The deuterium label from dual isotopically labelled water is lost from the body only in water, while the label in 18O is lost on both water and carbon dioxide. Measuring the rate of loss of both isotopes from body fluids permits estimation of the total amount of carbon dioxide produced over a period of 14 days or more, and so permits estimation of total energy expenditure over this period.
Physical Activity Ratio (PAR) is the energy expended in a given physical activity expressed as a multiple of the BMR. Very light activities have a PAR of between 1.0 - 1.4 times BMR; very heavy physical activity may have a PAR as high as 6 - 8 times BMR.
Physical Activity Level (PAL) is the sum of the PAR for each activity during the day x fraction of 24 hours spent in that activity, expressed as multiple of BMR .
Diet Induced Thermogenesis (DIT) is the increase in metabolic rate after a meal. It is the energy expenditure for synthesis and secretion of digestive enzymes, active transport for the absorption of the products of digestion and, most importantly, the synthesis of body reserves of metabolic fuel. Altogether it may represent 10 - 15% of the energy yield of a meal.
BMR is higher in men than in women of the same body weight and age because women have higher reserves of adipose tissue than do men of the same weight.
BMR falls with increasing age, even if body weight remains unchanged because of changes in body composition. There is a gradual loss of active muscle with increasing age, and the development of larger reserves of triacylglycerol between muscle fibres.
The main metabolic fuels are glucose, fatty acids (either as free (non-esterified) fatty acids in the circulation or triacylglycerol in plasma lipoproteins) and ketone bodies.
Ideally the diet should provide 55% of energy from carbohydrate, 30% from fat and 15% from protein. (Average western diets provide more fat than this, about 40%, and this is associated with obesity and increased risk of cardiovascular disease and cancer) .
In the fed state glucose will be the main fuel for all tissues. Glucose in excess of immediate requirements for tissues will be used in liver and muscle to synthesise the storage carbohydrate, glycogen. It will be also used in liver and muscle to synthesise fatty acids and triacylglycerol.
In the fasting state liver glycogen is used to provide a source of glucose initially. Muscle glycogen is mainly required as a fuel for muscle itself in vigorous exercise, but can provide a source of blood glucose indirectly.
As glycogen reserves begin to be depleted, glucose is synthesised from amino acids liberated by tissue protein catabolism (the process of gluconeogenesis).
The triacylglycerol reserves in adipose tissue are hydrolysed by an intracellular lipase (hormone sensitive lipase), liberating free (non-esterified) fatty acids and glycerol. The glycerol is taken up by the liver and is a substrate for gluconeogenesis. The fatty acids are taken up by tissues and used as a metabolic fuel. Fatty acids can never be a substrate for gluconeogenesis.
Fatty acids will dissolve in cell membranes and lyse them; binding them to serum albumin prevents this happening
Fatty acids in free solution would react with the free ionised calcium in the bloodstream; the calcium salts of fatty acids are insoluble. Again binding fatty acids to serum albumin prevents them reacting with calcium.
Muscle has a limited capacity for fatty acid oxidation, and cannot oxidise enough fatty acids to meet all of its energy needs. By contrast, the liver can oxidise more fatty acids than it needs to meet its own energy requirements. The liver metabolises fatty acids to acetyl CoA in excess of its needs for acetyl CoA, then synthesises acetoacetate and hydroxybutyrate for export to other tissues as an additional metabolic fuel.
The ketone bodies acetoacetate and hydroxybutyrate are synthesised in the liver. Acetone arises by non-enzymic breakdown of acetoacetate. It is poorly metabolised, and formation of acetone represents a loss of potentially valuable triacylglycerol reserves.
In extrahepatic tissues, hydroxybutyrate is oxidised back to acetoacetate, which is then cleaved to yield 2 mol of acetyl CoA for oxidation in the mitochondria. The oxidation of hydroxybutyrate to acetoacetate yields NADH, which is re-oxidised in the mitochondrial electron transport chain, yielding an additional ~2.5 ATP. Thus the liver effectively exports additional reducing power, which yields additional ATP, when it reduces acetoacetate to hydroxybutyrate.
In relatively prolonged starvation, when the concentration of ketone bodies is high enough for them to be a significant fuel for the brain, there is less demand for glucose, and the blood glucose concentration falls somewhat. There is still a need to provide glucose for red blood cells, since they lack mitochondria, and so cannot metabolise ketone bodies.
Insulin is the main hormone of the fed state. It is secreted by the beta-cells of the pancreatic islets in response to an increase in the blood concentration of glucose. In response to a decrease in the blood concentration of glucose, insulin secretion falls, and there is increased secretion of glucagon by the alpha-cells of the pancreatic islets.
The key roles of insulin are in the stimulation of synthesis of reserves of glycogen, fatty acid and triacylglycerol in the fed state.
The key roles of glucagon are in the mobilisation of metabolic fuels from these reserves.
In the fasting state the glucose transporters in muscle and adipose tissue are in intracellular vesicles. In response to insulin these vesicles migrate to the cell surface and fuse with the cell membrane, so inserting glucose transporters into the cell membrane. Under these conditions muscle and adipose tissue can take up glucose - for metabolism as the main fuel and synthesis of glycogen in muscle, and for synthesis of fatty acids and triacylglycerol in adipose tissue. As insulin secretion falls, and glucagon secretion increases in response to lower blood glucose concentration, so the transporters are internalised again, so that muscle and adipose tissue can no longer take up glucose. This means that in the fasting state muscle and liver do not take up glucose, so sparing it for use by the brain and red blood cells.
The liver can take up or release glucose, depending on the body's needs.
In the fed state the liver takes up glucose by trapping it intracellularly as glucose 6-phosphate. There are two isoenzymes in the liver that catalyse the phosphorylation of glucose to glucose 6-phosphate. One, hexokinase, has a low Km, and is saturated, and therefore acting at its maximum rate, at a very low concentration of glucose. The other, glucokinase, has a high Km (about 20 mmol /L) and so its activity increases as the concentration of glucose entering the liver cell increases.
The main contributor to diet-induced thermogenesis is the high ATP cost of synthesising glycogen, fatty acid and triacylglycerol, and protein.