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Percentage contribution to total energy

34%

66%

accounted for accounted for

*These figures assume complete oxidation whereas, as discussed in the text, this is not completely true for either glucose or non-esterified fatty acids.

Glucose turnover delivers about one-third, and non-esterified fatty acid turnover about two-thirds, of the energy delivery to tissues calculated in this way. Even this overemphasises the contribution of glucose, since a proportion of that glucose (perhaps 20-30%) will not be completely oxidised, but will be returned as lactate. Thus, we see that non-esterified fatty acids contribute an important energy source in the postabsorptive state.

sues, predominantly skeletal muscle and liver (Fig. 6.10). As we have seen, the rate of liberation from adipose tissue reflects mainly the activity of the enzyme hormone-sensitive lipase. What is the stimulus for activation of this enzyme, in comparison with the state after last evening's supper? Unfortunately the answer is not entirely clear, but a major component is undoubtedly the fall in insulin concentration. Since insulin suppresses the activity of hormone-sensitive lipase (see Box 2.4), a fall in insulin concentration will in itself lead to activation. In addition it is probable that the enzyme is activated by the influence of adrenaline in the plasma and noradrenaline released from sympathetic nerve terminals within adipose tissue.

Ketone bodies

Ketone bodies

Fig. 6.10 The pattern of non-esterified fatty acid (NEFA) metabolism after an overnight fast. Fatty acids are released by the action of hormone-sensitive lipase on the triacylglycerol (TAG) stores in adipose tissue. VLDL: very-low-density lipoprotein.

Renal cortex and other oxidative tissues

Fig. 6.10 The pattern of non-esterified fatty acid (NEFA) metabolism after an overnight fast. Fatty acids are released by the action of hormone-sensitive lipase on the triacylglycerol (TAG) stores in adipose tissue. VLDL: very-low-density lipoprotein.

The rate of non-esterified fatty acid release from adipose tissue is also regulated by the process of fatty acid re-esterification within the tissue (see Fig. 4.17). However, the process of re-esterification requires glycerol 3-phos-phate produced from glycolysis, and this will be occurring at a relatively low rate, so most of the fatty acids will escape from the adipocyte. The best estimates available suggest that around 10% of the fatty acids released by hormone-sensitive lipase action are retained by re-esterification in the overnight-fasted state, but this figure falls to near zero if the fast extends another few hours.

No discussion of fat metabolism is complete without some mention of the ketone bodies. These metabolites are produced during the hepatic oxidation of fatty acids (see Fig. 4.5) and released into the blood. Their production is favoured in states of relatively low insulin/glucagon ratio. After an overnight fast their concentration in blood is low - usually less than 0.2 mmol/l for 3-hydroxybutyrate and acetoacetate combined. Their turnover is rapid, however - typically 0.25-0.30 mmol/minute per person. In 'energy' terms, oxidation of these ketone bodies would contribute around 750-8 00 kJ/day (if this rate of ketone body turnover were continued throughout 24 hours) or perhaps 8% of total resting energy expenditure. This contribution increases markedly during more prolonged starvation.

6.2.4 Breakfast

The effects of a meal on non-esterified fatty acid and triacylglycerol metabolism may be quite different. Initially it will be simplest, as before, to consider a mainly carbohydrate breakfast and its effects on non-esterified fatty acid metabolism. Then we shall see how a fatty meal - for instance, fried bacon and eggs - affects the responses.

6.2.4.1 Non-esterified fatty acid metabolism after breakfast

As the meal is absorbed, so the rising glucose concentration stimulates insulin secretion and the concentration of insulin in the plasma rises. This has a direct suppressive effect on the enzyme hormone-sensitive lipase. The dose-response curve for this process is such that relatively low concentrations of insulin almost maximally suppress hormone-sensitive lipase; the half-maximal suppression is seen at around 120 pmol/l of insulin, and at the peak of insulin after a typical carbohydrate breakfast (say 400 -500 pmol/l) hormone-sensitive lipase will be maximally suppressed. Its activity does not appear to be completely suppressed whatever the insulin concentration, so some hydrolysis of stored triacylglycerol proceeds within adipose tissue. However, the rising glucose and insulin concentrations will also increase adipose tissue glucose uptake and glycolysis, and therefore production of glycerol 3 -phosphate and re-esterification of fatty acids within the tissue (see Fig. 4.17). Thus, release of non-esterified fatty acids from adipose tissue will be almost completely suppressed after a meal, and the plasma non-esterified fatty acid concentration will fall markedly, from its postab-sorptive level of around 0.5 mmol/l to less than 0.1 mol/l (Fig. 6.9). Notice that the variations in plasma non-esterified fatty acid concentration are much greater than those in plasma glucose; the organism appears to have no 'need' to regulate the plasma non-esterified fatty acid concentration more precisely, other than avoiding the hazards of particularly elevated concentrations.

The fall in plasma non-esterified fatty acid concentration affects the metabolism of tissues that use fatty acids as an oxidative fuel after the overnight fast. Skeletal muscle is a good example. As discussed earlier (Section 4.3.3.2), the rate of uptake of non-esterified fatty acids by muscle is a function primarily of fatty acid delivery - i.e. plasma concentration and blood flow. On the other hand, when glucose becomes available in the plasma after a meal, its utilisation is stimulated by the rise in insulin concentration. The muscle has no direct way of turning off fatty acid utilisation, but the coordinated control of metabolism in the whole body leads instead to its supply being cut off.

Along with the reduction in plasma non-esterified fatty acid concentration there is a switch in liver metabolism, also brought about by the increased insulin/glucagon ratio, leading to a reduction in the rate of ketone body formation and release. The blood ketone body concentration will therefore fall, typically from about 0.1-0.2 mmol/l after overnight fast to almost undetectably low levels - perhaps around 0.02 mmol/l. Their importance as a fuel decreases in proportion, so that ketone bodies are quite unimportant in the fed state.

As the absorptive phase declines after about 3-5 hours, so insulin concentrations begin to decline and the restraint of fat mobilisation is relaxed; plasma non-esterified fatty acid concentrations rise again (Fig. 6.9).

6.2.4.2 Triacylglycerol

If the meal contains a significant amount of fat, it will produce additional responses. However, the processing of dietary fat does not directly affect the coordinated responses of the glucose/non-esterified fatty acid insulin/glucagon system already described.

Consider a meal containing both carbohydrate and fat - say around 30 g of fat and 50 g carbohydrate - for example, a cheese sandwich. The plasma glucose and insulin concentrations will rise as described before, and the release of non-esterified fatty acids from adipose tissue will be suppressed so that their concentration in plasma falls. Dietary fat is almost entirely in the form of tria-cylglycerol (usually more than 95% is triacylglycerol). This is absorbed in the small intestine and processed in the intestinal cells to produce chylomicron particles, which are liberated into the bloodstream through the lymphatic system. This process is much slower than the absorption of glucose or amino acids, so that the peak in plasma triacylglycerol concentration after a fatty meal does not occur until 3 -5 hours after the meal. As chylomicron-triacylglycerol enters the plasma, the large, triacylglycerol-rich particles give the plasma a 'milky' appearance (Fig. 6.11).

A typical postabsorptive plasma triacylglycerol concentration of 1.0 mmol/l might rise to 1.5 mmol/l, or perhaps 2.0 mmol/l after a particularly fatty meal (Fig. 6.12). The total amount of triacylglycerol in the plasma (volume around

Fig. 6.11 The milky appearance of blood plasma (right) after a fatty meal, compared with its clear appearance in the fasted state (left). The turbidity is caused by the presence of the large chylomicron particles.

Fig. 6.12 Concentrations of triacylglycerol (TAG) in whole plasma (solid circles) and in chylomicrons (open circles) after overnight fast and after meals (shown by the arrows) containing either 33 g fat (a typical mixed meal) or 80 g fat (a high-fat meal) in groups of normal subjects. Data from Griffiths et al. (1994) and Coppack et al. (1990).

Fig. 6.12 Concentrations of triacylglycerol (TAG) in whole plasma (solid circles) and in chylomicrons (open circles) after overnight fast and after meals (shown by the arrows) containing either 33 g fat (a typical mixed meal) or 80 g fat (a high-fat meal) in groups of normal subjects. Data from Griffiths et al. (1994) and Coppack et al. (1990).

3 litres) at 1 mmol/l, with a Mr of about 900, is about 3 x 900 = 2700 mg or 2.7 g. Thus, again, the amount eaten (typically 30-40 g in a meal) would be sufficient to raise the plasma triacylglycerol concentration many times, but the rise is minimised by coordinated regulation of the mechanisms for its disposal.

The proportional rise in plasma triacylglycerol concentration after a meal is also lessened by the fact that only a small proportion of the plasma triacylglyc-erol represents that in chylomicrons. The plasma chylomicron-triacylglycerol concentration will rise from near zero to perhaps 0.3 - 0.4 mmol/l after a very fatty meal, a big percentage change (Fig. 6.12). The absolute rise (in mmol/l) in total plasma triacylglycerol is usually greater than the rise in chylomicron-tria-cylglycerol concentration because there is also an increase in concentration of other lipoproteins containing triacylglycerol, but still the proportional increase is smaller than might be expected.

The route of absorption of dietary fat means that, alone amongst nutrients, it escapes the liver on its entry into the circulation. In fact most of the triacyl-glycerol is removed from chylomicrons in tissues outside the liver, particularly adipose tissue and (to a lesser extent) skeletal muscle and heart. Adipose tissue contains the enzyme lipoprotein lipase in its capillaries, and this is the enzyme responsible for hydrolysis of the chylomicron-triacylglycerol (see Fig. 4.16). The activity of lipoprotein lipase is stimulated by insulin (see Fig. 4.15), so that it will be increased after the meal. Insulin stimulation of lipoprotein lipase in adipose tissue is a complex process involving both increased gene transcription and increased export of an active form of the enzyme from adipocytes to en-dothelial cells, and lipoprotein lipase activity in adipose tissue does not reach its peak until around 3-4 hours of insulin stimulation. It is surely no coincidence that this leads to peak lipoprotein lipase activity coinciding with the entry of chylomicron-triacylglycerol into the plasma; this represents another facet of the remarkable way in which insulin coordinates metabolism of different fuels in different tissues after a meal.

Lipoprotein lipase in adipose tissue hydrolyses the chylomicron-triacyl-glycerol, leading to the liberation of fatty acids which for the most part enter the adipocytes and are esterified to form new triacylglycerol for storage. This process is facilitated by the fact that hormone-sensitive lipase activity is suppressed after the meal, and fatty acid esterification increased by the increased insulin and glucose concentrations (and thus increased glycolytic flux, and glycerol 3-phosphate production). The concentration gradient of fatty acids will therefore be in favour of their storage rather than diffusion out of the tissue. In this way, the metabolism of triacylglycerol is influenced by the metabolism of glucose and non-esterified fatty acids.

Adipose tissue is not the only tissue that expresses lipoprotein lipase. In skeletal muscle, the enzyme is regulated in different ways. Insulin has a suppres-sive effect on muscle lipoprotein lipase, although this is fairly weak; it is also, like the stimulation of lipoprotein lipase in adipose tissue, rather slow, taking a matter of hours. Muscle lipoprotein lipase activity is influenced mainly by the fitness of the muscle for aerobic exercise. It is present at higher activity in red (oxidative) than white (glycolytic) fibres (see Table 4.1), and its activity is increased by exercise training. These features all suggest that the role of muscle lipoprotein lipase is not so much storage of fat, as utilisation of fat from plasma for energy production. The amount of chylomicron-triacylglycerol removed in skeletal muscle is not definitely known; it is likely to be rather less than the amount removed by adipose tissue in most people, but this might be very different in a fit, muscular person with less adipose tissue than average. The cellular organisation is just the same as in adipose tissue: the enzyme is present not in the muscle cells themselves, but attached to the endothelial cells lining the capillaries. It hydrolyses circulating lipoprotein-triacylglycerol (mainly chylomicron-triacylglycerol for the present discussion), liberating fatty acids which reach the muscle cells along some sort of structured diffusion pathway. Muscle is not a tissue in which triacylglycerol is stored for the rest of the body (although muscle cells do contain intracellular triacylglycerol stores) and most fatty acids entering muscle cells are oxidised. However, there is evidence, from experiments with chylomicrons containing isotopically labelled fatty acids, that chylomicron-triacylglycerol fatty acids which are taken up by muscle are largely esterified. Presumably this is how the muscle cells replenish their own local triacylglycerol store for energy production at a later time. It is only fair to say, however, that we understand very little of the regulation of lipoprotein-triacylglycerol utilisation by muscle.

The pattern of triacylglycerol metabolism after a meal containing fat is illustrated in Fig. 6.13.

Fig. 6.13 The pattern of plasma triacylglycerol metabolism after a breakfast containing both fat and carbohydrate. Triacylglycerol (TAG) enters the circulation in the form of chylomicron particles and is hydrolysed by the enzyme lipoprotein lipase (LPL) in the capillaries of tissues (see Fig. 4.16 for more details of this process).

Fig. 6.13 The pattern of plasma triacylglycerol metabolism after a breakfast containing both fat and carbohydrate. Triacylglycerol (TAG) enters the circulation in the form of chylomicron particles and is hydrolysed by the enzyme lipoprotein lipase (LPL) in the capillaries of tissues (see Fig. 4.16 for more details of this process).

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