The period of adaptation to starvation

The changes listed in Table 8.2 come into place gradually over the first three weeks or so of total starvation; this is the period of adaptation.

8.3.2.1 Hormonal changes

Blood glucose concentrations fall very gradually in prolonged starvation and they are followed by the plasma insulin concentration. Glucagon concentrations, on the other hand, rise, so that the ratio of insulin/glucagon reaching the liver must change considerably from early to late starvation. The plasma leptin concentration also falls. In longer starvation this may be due to a reduction in adipose tissue mass, but in the shorter term it also reflects a 'sensing' of energy deficit in adipose tissue, perhaps through reduced insulin concentrations (insulin will acutely stimulate leptin secretion from adipose tissue after feeding).

The onset of starvation is also marked by a decrease in the level of the active thyroid hormone, triiodothyronine (T3, see Fig. 5.8), in the blood (Fig. 8.4). Several factors appear to cause this. The early reduction in secretion of thyroid hormones has been attributed to the fall in leptin action on the hypothalamus (reducing thyroid-stimulating hormone secretion from the anterior pituitary, and hence thyroid hormone secretion). Therefore, although this may appear to be a central effect, it arises in turn from 'peripheral' sensing of fuel shortage. There is also a shift towards production of an inactive form, reverse triiodothyronine (reverse T3), at the expense of T3 (Fig. 8.4). The effect of the fall in T3 concentration is to reduce overall metabolic rate, and to reduce the rate of proteolysis in muscle. The reduction in overall metabolic rate leads, of course, to a decrease in the rate of depletion of the body's fuel stores. However, it is unlikely that the metabolism of the brain, usually the largest glucose consumer, is reduced significantly, so the need for glucose is still present; it is reduced, however, by the mechanisms described below.

Both the sympathetic nervous system and the adrenal medulla play some role during starvation. However, although starvation is a state in which fuel mobilisation is required, the adrenergic systems play a much lesser role than in other, more stress-driven states (such as exercise). There is some activation of both sympathetic nervous system and adrenaline secretion during the first week or so of starvation. These changes would normally cause an elevation in overall

Pylori And Species

Fig. 8.4 Serum concentrations of triiodothyronine (T3) and reverse triiodothyronine (reverse-T3) during early starvation in normal volunteers. Based on Gardner et al. (1979).

Hours of fasting

Fig. 8.4 Serum concentrations of triiodothyronine (T3) and reverse triiodothyronine (reverse-T3) during early starvation in normal volunteers. Based on Gardner et al. (1979).

metabolic rate; this is not seen, since it is outweighed by the reduction in T3 concentration. On the other hand, the adrenergic systems are probably important in stimulation of lipolysis in adipose tissue. This latter will be reinforced by the continuing reduction in insulin concentration. Therefore, the plasma non-es-terified fatty acid concentration rises during the adaptation period (Fig. 7.5).

8.3.2.2 Adaptation of fatty acid, ketone body and glucose metabolism

The elevation in plasma non-esterified fatty acid concentration leads to a number of adaptations. Skeletal muscle will use non-esterified fatty acids almost entirely in preference to glucose for its energy production. In the liver, the rate of fatty acid esterification, usually stimulated by insulin, will decrease; fatty acids will be diverted into oxidation (glucagon stimulates this pathway). This diversion is mediated in part by a decrease in hepatic malonyl-CoA concentration, a result of the decrease in insulin concentration (see Fig. 4.3). Increased oxidation of fatty acids leads to increased production of the ketone bodies, 3-hydroxybutyrate and acetoacetate (see Figs 4.3, 4.5). These can be used as an oxidative fuel by many tissues, at a rate simply depending on their concentration in the blood. Most importantly, they can be used by the brain. This is a crucial feature of the response to starvation: the brain begins to use a fuel derived from the body's fat stores, in preference to glucose. By the end of the third week of starvation, blood ketone body concentrations may reach 6 -7 mmol/l, compared with < 0.2 mmol/l normally (Fig. 7.5). At this stage, ketone body oxidation can account for approximately two-thirds of the oxygen consumption of the brain. Thus, about 70-80 g per day of glucose is spared oxidation.

The body's need to form new glucose from amino acids is also reduced by the stimulation of gluconeogenesis in the liver, enabling glucose to be efficiently recycled. Glycolytic cells and tissues such as erythrocytes and the renal medulla will still need to use glucose. (They cannot use ketone bodies since they do not have the oxidative capacity.) Glycolysis in these tissues, however, leads to the release of lactate that is returned to the liver and avidly reconverted into glucose (the Cori cycle, see Fig. 6.20). Thus, the glucose that must be used by these tissues is recycled. Energy for this process comes from the increased oxidation of fatty acids in the liver, forming the NADH necessary to drive gluconeogenesis. This means that, in effect, the glycolytic tissues run on energy derived from the fat stores.

8.3.2.3 Sparing of muscle protein

By the mechanisms described above, the need to produce glucose from muscle protein is reduced, and the loss of nitrogen in the urine decreases. However, with the insulin concentration decreasing, the net stimulus would seem to be for increasing muscle protein breakdown. How is the sparing of muscle protein brought about?

The possible role of the decreasing T3 concentration has been mentioned: T3 usually has the effect of stimulating muscle proteolysis (see Section 6.3.3, Fig. 6.19). Another possibility is that the increase in plasma adrenaline concentration may be involved: adrenergic drugs have an anabolic effect on muscle (see Section 6.3.3), although this effect is not clearly understood, and the receptors by which it is mediated have not been delineated.

The other possible mediator is the increase in blood ketone body concentration. Some experimental studies show that elevation of the blood ketone body concentration leads to a reduction in the net breakdown of muscle protein. There is a possible mechanism. The branched-chain amino acids are catabolised in muscle by transamination, followed by the action of branched-chain 2-oxo-acid dehydrogenase (see Section 6.3.2.2). This enzyme complex has many similarities with pyruvate dehydrogenase. Like pyruvate dehydro-genase, its activity is inhibited by a high acetyl-CoA/CoASH ratio. In other words, if the muscle is plentifully supplied with other substrates for oxidation (such as fatty acids and ketone bodies, in starvation) then the oxidation of the branched-chain amino acids will be suppressed.

However, another way of looking at the fall in nitrogen loss in starvation is that it may be another facet of the general slowing down of metabolism. In this case no specific mechanism need be postulated. This has been discussed by Henry et al. (1988), who argue that conventional understanding of the response to starvation is heavily biased since it is based mainly on obese subjects undergoing starvation for the purpose of weight reduction.

8.3.2.4 Kidney metabolism

During this period of starvation, there are marked changes in the metabolic pattern of the kidney that will be briefly discussed here. The concentrations of lipid-derived fuels - non-esterified fatty acids and ketone bodies - are high in the plasma, as shown in Fig. 8.5. Each of these is a biological acid. Therefore, the production of hydrogen ions increases and the pH of the blood tends to fall. In order to counter this, the body must excrete excess hydrogen ions. In Section 6.3.2.3 one means for achieving this was mentioned: the kidney can excrete ammonia, which carries with it one hydrogen ion (since it will be in the form of NH4+). The ammonia may be derived from the action of glutaminase on glutamine, and glutamate dehydrogenase on glutamate, in the kidney (see Section 6.3.2.3). The renal uptake of glutamine increases in starvation in order to provide a means for excretion of excess hydrogen ions. Glutamine metabolism in the kidney can lead to glucose production, especially during starvation, when the kidney can become an important gluconeogenic tissue. Thus, again we see the efficiency of metabolism: a metabolic process (ammonia excretion) necessary to regulate blood pH is coupled with the conversion of a muscle-derived amino acid to glucose.

Time of fasting (days)

Fig. 8.5 Concentrations of non-esterified fatty acids (NEFA) and ketone bodies (the sum of acetoacetate and 3-hydroxybutyrate) in blood in obese subjects during starvation. Based on Owen, O.E., Tappy, L., Mozzoli, M.A. & Smalley, K.J. (1990) Acute starvation. In: The Metabolic and Molecular Basis of Acquired Disease Vol. 1 (eds Cohen, R.D., Lewis, B., Alberti, K.G.M.M. & Denman, A.M.), 550-570. With permission of the publisher W.B. Saunders.

Time of fasting (days)

Fig. 8.5 Concentrations of non-esterified fatty acids (NEFA) and ketone bodies (the sum of acetoacetate and 3-hydroxybutyrate) in blood in obese subjects during starvation. Based on Owen, O.E., Tappy, L., Mozzoli, M.A. & Smalley, K.J. (1990) Acute starvation. In: The Metabolic and Molecular Basis of Acquired Disease Vol. 1 (eds Cohen, R.D., Lewis, B., Alberti, K.G.M.M. & Denman, A.M.), 550-570. With permission of the publisher W.B. Saunders.

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Responses

  • anja
    What is metabolic adaptation to prolonged starvation?
    11 months ago
  • Segan
    How does the body adapt to starvation?
    9 months ago

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