Energy Production

The body derives energy from the metabolism of carbohydrate, fat, and protein provided exogenously in the fed state and endogenously in the postabsorp-tive state. A mixture of metabolic fuels, including glucose, triacylglycerols, ketone bodies, nonesteri-fied fatty acids, alcohol, and amino acids, are present in the circulation. The proportion of these energy substrates in the blood at any one time depends on the fed or fasting state of the individual, the extent of fuel stores, and recent or current metabolic demand. In a normal, nonobese, 70-kg adult there are approximately 500 MJ (120 000kcal) contained in adipose tissue, 100 MJ (24 000kcal) stored in muscle and visceral proteins, and 4.2 MJ (1000 kcal) stored as liver and muscle glycogen. During a normal day, half of the total energy requirement is met by carbohydrate metabolism. At this rate, glycogen stores would be exhausted after 1 or 2 days of fasting. However, glycogen stores are maintained for a longer period due to the production of glucose from gluconeogenesis (Figure 1).

Carbohydrate metabolism Glucose plays a key role in body metabolism. It is the preferred metabolic fuel for many tissues and is an essential fuel for the retina, red blood cells, the renal medulla, and the brain under normal conditions. In the fed state, glucose is derived from the digestion and absorption of carbohydrates provided in the meal. To produce energy from glucose, three metabolic pathways are involved (Figure 2). Glucose is first oxidized to form pyruvate via the glycolytic pathway. Pyruvate then enters the Krebs cycle and is completely oxidized to form NADH + H, FADH2, and carbon dioxide. The NADH + H transports hydrogen to the respiratory chain, where it is used to reduce oxygen to water. The net yield of energy from the metabolism of 1 molecule of glucose is 38 molecules of ATP.

DIET

DIET

Kidney

Urine glucose: if plasma glucose >180 mg /dl

Figure 1 The metabolism of energy substrates to maintain glucose homeostasis.

Kidney

Urine glucose: if plasma glucose >180 mg /dl

Figure 1 The metabolism of energy substrates to maintain glucose homeostasis.

Because of the strict glucose requirements of the brain, the circulating blood glucose pool is tightly controlled at approximately 16 g. Three important mechanisms are responsible for this regulation:

1. Insulin enhances glucose uptake into muscle and fat and stimulates glycogen synthesis. It also inhibits lipolysis, glycogenolysis, and gluconeogenesis. High insulin levels will decrease blood glucose levels. Conversely, low insulin levels will cause a rise in blood glucose by decreased inhibition of glycogen-olysis and reduced peripheral uptake of glucose.

2. Glucagon increases liver glycogen breakdown, glu-coneogenesis, and ketogenesis from fatty acids. It also stimulates lipolysis from adipocytes in extra-hepatic tissue. The net result of glucagon activity is an increase in blood glucose concentration that helps to maintain blood glucose levels despite the effect of insulin.

3. Neuroendocrine responses to glucose deprivation in the brain act to rapidly increase glucose release from liver glycogen.

The fed state is characterized by increased blood concentrations of glucose, amino acids, and fat. Insulin secretion is stimulated while glucagon levels remain unchanged or are decreased. As a result, there is increased glucose uptake into tissues and enhanced glycogen, protein, and triacylglycerol synthesis. Glu-cagon balances this effect by stimulating glycogen breakdown to maintain blood glucose levels. By this mechanism, blood glucose levels are controlled during periods of surplus carbohydrate ingestion and excess glucose is stored as glycogen or fat.

Glycogen is a complex hydrated polymer of glucose arranged in a highly branched, spherical form. It allows

Glucose

Dihydroxyacetone phosphate

Glucose 6-phosphate t

Fructose 6-phosphate |^ATP

Fructose 1,6-biphosphate t

Glyceraldehyde 3-phosphate t—

1,3-Bisphosphoglycerate

2NADH+H

2ATP

3-Phosphoglycerate Î

2-Phosphoglycerate

Phosphoenolpyruvate 2ATP

Lactate

Pyruvate

CYTOSOL

GLYCOLYSIS

2CO2

4ATP

2FADH

Oxaloacetate

Malate /

Fumarate

-2NADH+H

Oxaloacetate

Acetyl-CoA

Citrate

Malate /

Fumarate

Isocitrate

KREBS CYCLE

MITOCHONDRION

Isocitrate

2NADH+H

2NADH+H

Succinate r

2ATP

Succinyl-CoA

Va-ketoglutarate '

10ATP 10ATP H2O

10ATP

2NADH+H

RESPIRATORY CHAIN

Figure 2 The production of energy from glucose via the glycolytic pathway, the Krebs cycle, and the respiratory chain.

glucose to be stored in large amounts without causing osmotic shifts. The terminal glucose molecules within this branching structure are accessible to the enzymes mediating glycogen breakdown to allow the rapid release of glucose in times of stress. The glycogen molecule expands in size after a carbohydrate-rich meal to approximately 40 nm in diameter and shrinks to 10 nm in diameter or less between meals. An adult male receiving a normal carbohydrate-containing diet has approximately 70 g of liver glycogen and 200 g of muscle glycogen. Glycogen is broken down by the enzyme phosphorylase. Glucose-6-phosphatase continues the breakdown of glycogen to glucose in the liver. Muscle glycogen is metabolized by anaerobic glycolysis to form pyruvate and lactate. Lactate is then transported to the liver, where it acts as a precursor for gluconeogenesis. This is called the Cori cycle (Figure 3). The Cori cycle contributes to approximately 40% of the normal plasma

Glycogen

Glucose 6-phosphate

Urea

Glucose

Glucose

Glycogen

Glucose 6-phosphate

Urea

MUSCLE

Lactate Pyruvate

Alanine Glutamine

Lactate Pyruvate

Alanine Glutamine

MUSCLE

Figure 3 The metabolism of muscle glycogen and protein to form glucose involving the Cori cycle (lactate to glucose) and the glucose-alanine cycle.

glucose turnover. It has the advantage of providing energy (net 3 molecules of ATP) without the loss of glucose molecules. The energy required for the resynthe-sis of glucose in the liver is derived from fatty acid oxidation. The total body glycogen stores can meet the needs of the brain for approximately 3 days. After this period, alternative sources of metabolic fuel must be found.

Protein metabolism Body nitrogen resides in two main compartments. Approximately half of the body's nitrogen is contained in extracellular tissues such as collagen. The nitrogen present within these tissues is relatively fixed and does not change significantly with starvation. The nitrogen turnover within this compartment can be assessed by the measurement of hydroxyproline excretion. The remaining nitrogen is present in the lean muscle mass, comprising skeletal and visceral muscle. The proteins within these tissues are constantly being broken down and resynthesized at a rate of 3-3.5 g/kg/day in a young adult. Measurement of urinary 3-methylhistidine excretion and creatinine excretion can be used to estimate the fractional catabolic rate of skeletal muscle.

Protein synthesis and degradation involves several independent metabolic systems. The autophagic-lysosomal pathway facilitates most of the proteolysis occurring in the body. Another pathway, the protea-some-ubiquitin system, plays a central role in the degradation of specific proteins. For example, the proteasome is involved in the rapid regulation of many rate-limiting enzymes. The proteasome also mediates the loss of skeletal muscle protein in starvation and wasting disorders. The 26S proteasome consists of a proteolytic core complex, the 20S

proteasome, and two 19S regulatory complexes. Substrates are conjugated with multiubiquitin chains before degradation. The autophagic-lysosomal system is regulated by plasma amino acid levels, whereas no such feedback mechanism has been demonstrated for the ubiquitin-proteasome pathway. The fatty acid, eicopentenoic acid, has been shown to downregulate ubiquitin-dependent proteo-lysis in mice after acute starvation. Furthermore, experimental data in starved rats suggest that ubiquitin-proteasome-dependent muscle proteolysis is ameliorated in response to insulin release and refeeding. The exact mechanisms involved in the regulation of ubiquitin-proteasome-dependent proteolysis are not completely understood.

Both autophagic-lysosomal and ubiquitin-protea-some pathways generate amino acids as their final product. Glutamine is the most abundant amino acid in humans. It is an important energy substrate for monocytes and the gut. Depletion of glutamine during starvation or chronic illness has been shown to inhibit the ubiquitin-proteasome proteolytic pathway and may contribute to impaired immune function of monocytes during starvation or critical illness.

In the fed state, amino acids digested and absorbed in excess of the body's immediate requirements for incorporation into proteins or other molecules are either oxidized for energy or metabolized to glycogen or fat. Protein provides approximately 17kJg-1 (4kcalg-1) of energy when metabolized as an energy source.

Prolonged fasting results in depletion of liver and muscle glycogen stores. In this clinical setting the conversion of amino acids to glucose contributes to the glucose requirements of the brain. The transition to metabolism of amino acids as an energy source is mediated by an alteration in the balance of insulin and glucagon. The breakdown of tissue protein to provide glucose results in a sustained loss of body nitrogen of approximately 12 g per day. Experimentally, this loss of body nitrogen can be prevented by the administration of glucose. As a result of muscle protein breakdown, amino acids, predominantly alanine and glutamine, are released into the circulation. However, the amount of alanine released exceeds the alanine content of the muscle protein. This is because approximately one-third of the alanine released from muscle originates directly from the muscle protein, whereas the remaining two-thirds is derived from pyruvate. Pyruvate is formed by the metabolism of muscle glycogen or by the transamination of other amino acids contained within the muscle protein. Alanine is then transported to the liver, where it is rapidly taken up and converted to glucose: This is known as the glucose-alanine cycle (Figure 3). Despite the increased release of alanine from muscle, plasma alanine levels decline in early fasting. This results from the rapid uptake and conversion of alanine by the liver.

Fat metabolism Fat is an efficient store of energy providing approximately 38kJg_1 (9kcalg_1). Fat is predominantly stored as triacylglycerols within adipocytes. The amount of fat stores may vary substantially among individuals. In the fed state, insulin stimulates triacylglycerol synthesis. During fasting, triacylglycerol is converted to fatty acids and gly-cerol (Figure 4). Within days, glycerol and palmitate release increases by two or three times fed levels. This release is regulated by hormone-sensitive lipase. Due to the absence of glycerol kinase in white adipose tissue, glycerol cannot be completely metabolized within the adipocytes and is transported to the liver, where it is converted to glucose by gluconeo-genesis. The fatty acids are either released from the adipocytes to be oxidized by the liver or other tissues or may be reesterified with glycerol 3-phosphate and reenter the cycle to form triacylglycerol (Figure 4). The energy cost of reesterification of fatty acids in starvation may account for 2 or 3% of the resting energy expenditure.

Oxidation of long-chain fatty acids (LCFAs) requires the mitochondrial carnitine system for transport into the mitochondrial matrix. This transport system consists of several enzymes, including the malonyl-coenzyme A (CoA)-sensitive carnitine palmitoyltransferase I (CPT-I), carnitine:acylcarni-tine translocase, and CPT-II. CPT-I is regulated at

Figure 4 The triacylglycerol-fatty acid cycle.

the transcriptional level by malonyl-CoA. Although carbohydrates are the major energy source during high-impact exercise, LCFAs are the preferred substrate during endurance exercise. In human skeletal muscle, during exercise free carnitine appears to play a greater regulatory role on LCFA oxidation than malonyl-CoA. However, some aspects of the transport of LCFAs to the inner mitochondrial matrix in humans are not completely understood.

Most of the acetyl-CoA produced from fatty acid oxidation is metabolized to acetoacetate, which in turn may be converted to /3-hydroxybutyrate and acetone. These products are known as ketone bodies. Acetyl-CoA is also converted to malonyl-CoA, catalyzed by the enzyme acetyl-CoA carboxy-lase. Although ketone bodies are produced in small quantities in the fed state, they are generally metabolized by the liver and are not released into the circulation. During fasting, the rate of production of acetoacetate and /3-hydroxybutyrate significantly increases. These metabolites are released into the circulation and can be used by the brain and other tissues as an alternative energy source.

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