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Physiology
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Lecture 2
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Lecture 4
Lecture 5
Lecture 6
Lecture 7
Lecture 8

Lecture 4

Basic Principles of Nutrient Metabolism:
Hormones, Protein, and Carbohydrate in the Adaptation to Starvation.

Protein Stores and Their Role in Survival
In the average 70 kg man, the largest store of calories is in the form of fat in adipose tissue with approximately 135,000 Calories stored 13.5 kg of adipose tissue. This storage compartment can be greatly expanded with long-term overnutrition in obese individuals. There are approximately 54,000 Calories stored as protein both in muscle and viscera. Only half of these calories can be mobilized for energy, since depletion below 50 percent of total protein stores is incompatible with life. In addition to being an energy source, protein plays a functional role in many organs including the liver, and depletion is associated with impaired immunity to infection. In fact, the most common cause of death in an epidemic of starvation is typically simple bacterial pneumonia. Conservation of protein is an adaptation tightly linked to survival during acute starvation.

There are only 1200 Calories stored as carbohydrate in liver and muscle glycogen. There are clear adaptive advantages to storing calories as fat, since fat can provide more energy per gram than carbohydrate or protein. However, since carbohydrate stores are so small, they are depleted in three days of uncomplicated starvation or sooner under conditions of increased energy expenditure. This dependence on fat and protein stores in starvation requires metabolic adaptations to minimize the loss of protein stores, and a shift to metabolic pathways predominantly utilizing the large fat stores available.

The Adaptation to Starvation
The postabsorptive period is defined as 8 to 16 hours after eating, and has been operationally defined as the timepoint after an overnight fast when a number of hormonal determinations can be made under standard conditions. It can be thought of as a period of very early adaptation to starvation. During this period, the primary metabolic priority is the provision of adequate glucose for essential functions of the brain, red blood cells, peripheral nerves, and renal medulla. During this postabsorptive phase, insulin levels fall as blood glucose falls from a range of 4 to 5 mmol/liter to 3 to 4 mmol/liter. Glucose is released from the liver into the circulation via glycogenolysis of stores accumulated after feeding under the influence of insulin. The fall in glucose levels is associated with the depletion of glycogen stores. Skeletal muscle does not release glucose from stored glycogen directly into the circulation, because myocytes lack the required enzyme, glucose-6-phosphatase. However, muscle releases lactate and amino acids such as alanine, which can enter the circulation and are converted to glucose in the liver via gluconeogenesis. Glucagon in the presence of lowered insulin concentrations promotes gluconeogenesis during the postabsorptive period.

In addition, glucagon in the presence of lowered insulin levels promotes lipolysis. As the stored triglyceride in adipocytes is mobilized as free fatty acids, those tissues that do not require glucose as their primary fuel (e.g. skeletal muscle) begin to oxidize free fatty acids. These changes during the early postabsorptive period act to increase free fatty acid oxidation in order to spare protein breakdown. During the first few days of starvation, free fatty acid concentrations increase from a range of 0.5 to 0.8 mmol/liter up to 1.2 to 1.6 mmol/liter, and plateau thereafter as starvation is prolonged. These free fatty acids circulate bound to albumin, and are oxidized in the liver to water soluble ketone bodies, including acetoacetate and beta-hydroxybutyrate. Following 4 to 6 weeks of uncomplicated starvation in obese subjects with more than adequate triglyceride stores, acetoacetate concentrations rise 25-fold and beta-hydroxybutyrate concentrations rise 100-fold from the levels observed in the postabsorptive phase. These are the largest fluctuations seen in any circulating fuel with prolonged starvation.

Protein synthesis and catabolism has been estimated to account for approximately 40 percent of resting energy expenditure. In addition, the changes in protein metabolism are critical to maintaining the body cell mass during starvation which directly impacts survival. Plasma amino acids measured in venous blood give non-specific indications of the adaptations taking place in protein metabolism during the course of starvation. In addition, the excretion of protein from the body as urinary urea nitrogen expressed as nitrogen balance provides further insights into overall protein nutriture.

The basic mechanisms underlying these adaptive changes in protein synthesis and degradation are still not completely understood. Proteolysis occurs in cellular lysosomes via autophagy. This process is stimulated by a shortage of critical regulatory amino acids including phenylalanine, tryptophan, methionine, leucine, tyrosine, glutamic acid, proline and histidine. While not conclusively established, it appears that decreased concentrations of specific amino acyl transfer RNA's for these amino acids trigger proteolysis. In terms of protein synthesis, there is a decrease in the amount and activity of RNA subunits involved in initiation, elongation, and termination of protein synthesis. Insulin is the primary hormone known to regulate protein metabolism. Insulin deficiency leads to net protein breakdown, and hyperinsulinemia under euglycemic conditions inhibits proteolysis. There is also evidence that glucagon participates in this regulatory process by stimulating splanchnic proteolysis. Plasma cortisol levels are increased for several hours and inhibit protein synthesis while increasing protein breakdown. Elevations in epinephrine, previously thought to increase protein breakdown lead to decreases in the rate of whole body protein breakdown. Growth hormone has been shown to increase protein synthesis but to oppose insulin's antiproteolytic effects. The role of insulin-like growth factor I is still not established. Recent studies have demonstrated that plasma amino acid levels and amino acid availability play an important role in modulating the rate of protein breakdown. The magnitude of these amino acid-mediated antiproteolytic effects were equivalent to those of insulin.

Impact of Protein Conservation
The impact of the adaptation to a fat fuel economy is reflected in the rapid changes in urinary nitrogen excretion reflecting net protein sparing through two processes. First, there is less protein breakdown. It has been estimated that protein synthesis decreases in the whole body by 40 per cent between the postprandial and postabsorptive phases with a further decrease over the first several days of starvation. Secondly, there is increased reutilization of nitrogen evidenced by decreased urea formation in the liver through the arginine-citrulline cycle. In obese subjects fasting for 7 days, protein breakdown and urinary urea nitrogen excretion decrease in parallel. Overall nitrogen is conserved so that nitrogen excretion decreases from 12 g/day in the postabsorptive state to 5 g/day seven to ten days later. This decrease translates into a decrease in muscle protein breakdown from 75 g/day to 20 g/day. Based on theoretical calculations of the time necessary to reach the critical 50 per cent of body cell mass, survival is extended through these adaptations from approximately 60 days to over 260 days provided that adequate fluid and electrolytes are administered.

Within seven to ten days of starvation, there is a marked adaptive decrease in energy expenditure. Normally, resting energy expenditure is proportional to lean body mass. However, after seven to ten days of starvation, there is a twenty per cent decrease in resting energy expenditure, at a time when lean body mass has decreased by less than five per cent. Changes in the peripheral metabolism of thyroid hormones occur which may contribute significantly to the observed decrease in energy expenditure. Among these changes, there is less production of triiodothyronine, the most metabolically active thyroid hormone, via a decreased activity of 5'monodeiodinase in the liver and other peripheral tissues. There is a reciprocal rise in reverse triiodothyronine, an inactive metabolite, while thyroxine levels remain constant. The overall decrease in energy expenditure with starvation is an adaptive change which results in a decreased rate of whole body lipolysis, proteolysis, and gluconegenesis. Aerobic exercise in obese dieters does not reverse this adaptive change in energy regulation.

There is a good correlation between the adaptive hormonal changes which occur during starvation, and the decrease in whole body protein breakdown which occurs as a result.

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