Many Metabolic Fuels Are Interconvertible

Carbohydrate in excess of immediate requirements as fuel or for synthesis of glycogen in muscle and liver may be used for lipogenesis (Chapter 21) and hence triacyl-glycerol synthesis in both adipose tissue and liver (whence it is exported in very low density lipoprotein). The importance of lipogenesis in human beings is unclear; in Western countries, dietary fat provides 35-45% of energy intake, while in less developed countries where carbohydrate may provide 60-75% of energy intake the total intake of food may be so low that there is little surplus for lipogenesis. A high intake of fat inhibits lipogenesis.

Fatty acids (and ketone bodies formed from them) cannot be used for the synthesis of glucose. The reaction of pyruvate dehydrogenase, forming acetyl-CoA, is irreversible, and for every two-carbon unit from acetyl-CoA that enters the citric acid cycle there is a loss of two carbon atoms as carbon dioxide before only one molecule of oxaloacetate is re-formed—ie, there is no net increase. This means that acetyl-CoA (and therefore any substrates that yield acetyl-CoA) can never be used for gluconeogenesis (Chapter 19). The (relatively rare) fatty acids with an odd number of carbon atoms yield propionyl-CoA as the product of the final cycle of P-oxidation (Chapter 22), and this can be a substrate for gluconeogenesis, as can the glycerol released by lipolysis of adipose tissue triacylglycerol reserves. Most of the amino acids in excess of requirements for protein synthesis (arising from the diet or from tissue protein turnover) yield pyruvate, or five- and four-carbon intermediates of the citric acid cycle. Pyruvate can be carboxylated to oxaloacetate, which is the primary substrate for gluconeogenesis, and the five- and four-carbon intermediates also result in a net increase in the formation of oxaloacetate, which is then available for gluconeogenesis. These amino acids are classified as glucogenic. Lysine and leucine yield only acetyl-CoA on oxidation and thus cannot be used for gluconeogen-esis, while phenylalanine, tyrosine, tryptophan, and isoleucine give rise to both acetyl-CoA and to intermediates of the citric acid cycle that can be used for gluco-

neogenesis. Those amino acids that give rise to acetyl-CoA are classified as ketogenic because in the starving state much of the acetyl-CoA will be used for synthesis of ketone bodies in the liver.


Glucose Is Always Required by the Central Nervous System & Erythrocytes

Erythrocytes lack mitochondria and hence are wholly reliant on glycolysis and the pentose phosphate pathway. The brain can metabolize ketone bodies to meet about 20% of its energy requirements; the remainder must be supplied by glucose. The metabolic changes that occur in starvation are the consequences of the need to preserve glucose and the limited reserves of glycogen in liver for use by the brain and erythrocytes and to ensure the provision of alternative fuels for other tissues. The fetus and synthesis of lactose in milk also require a significant amount of glucose.

In the Fed State, Metabolic Fuel Reserves Are Laid Down

For several hours after a meal, while the products of digestion are being absorbed, there is an abundant supply of metabolic fuels. Under these conditions, glucose is the major fuel for oxidation in most tissues; this is observed as an increase in the respiratory quotient (the ratio of carbon dioxide produced to oxygen consumed) from about 0.8 in the starved state to near 1 (Table 27-1).

Glucose uptake into muscle and adipose tissue is controlled by insulin, which is secreted by the B islet cells of the pancreas in response to an increased concentration of glucose in the portal blood. An early response to insulin in muscle and adipose tissue is the migration of glucose transporter vesicles to the cell surface, exposing active glucose transporters (GLUT 4). These insulin-sensitive tissues will only take up glucose from the blood stream to any significant extent in the presence of the hormone. As insulin secretion falls in the starved state, so the transporters are internalized again, reducing glucose uptake.

The uptake of glucose into the liver is independent of insulin, but liver has an isoenzyme of hexokinase (glucokinase) with a high Km, so that as the concentration of glucose entering the liver increases, so does the rate of synthesis of glucose 6-phosphate. This is in excess of the liver's requirement for energy and is used mainly for synthesis of glycogen. In both liver and skeletal muscle, insulin acts to stimulate glycogen syn-thase and inhibit glycogen phosphorylase. Some of the glucose entering the liver may also be used for lipogene-sis and synthesis of triacylglycerol. In adipose tissue, insulin stimulates glucose uptake, its conversion to fatty acids, and their esterification; and inhibits intracellular lipolysis and the release of free fatty acids.

The products of lipid digestion enter the circulation as triacylglycerol-rich chylomicrons (Chapter 25). In adipose tissue and skeletal muscle, lipoprotein lipase is activated in response to insulin; the resultant free fatty acids are largely taken up to form triacylglycerol reserves, while the glycerol remains in the blood stream and is taken up by the liver and used for glycogen synthesis or lipogenesis. Free fatty acids remaining in the blood stream are taken up by the liver and reesterified. The lipid-depleted chylomicron remnants are also cleared by the liver, and surplus liver triacylglycerol— including that from lipogenesis—is exported in very low density lipoprotein.

Under normal feeding patterns the rate of tissue protein catabolism is more or less constant throughout the day; it is only in cachexia that there is an increased rate of protein catabolism. There is net protein catabo-lism in the postabsorptive phase of the feeding cycle and net protein synthesis in the absorptive phase, when the rate of synthesis increases by about 20-25%. The increased rate of protein synthesis is, again, a response to insulin action. Protein synthesis is an energy-expensive process, accounting for up to almost 20% of energy expenditure in the fed state, when there is an ample supply of amino acids from the diet, but under 9% in the starved state.

Metabolic Fuel Reserves Are Mobilized in the Starving State

There is a small fall in plasma glucose upon starvation, then little change as starvation progresses (Table 27-2; Figure 27-2). Plasma free fatty acids increase with onset of starvation but then plateau. There is an initial delay in ketone body production, but as starvation progresses the plasma concentration of ketone bodies increases markedly.

In the postabsorptive state, as the concentration of glucose in the portal blood falls, so insulin secretion decreases, resulting in skeletal muscle and adipose tissue taking up less glucose. The increase in secretion of glucagon from the A cells of the pancreas inhibits glycogen synthase and activates glycogen phosphorylase in liver. The resulting glucose 6-phosphate in liver is

Figure 27-1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of preference: (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase; FFA, free fatty acids; VLDL, very low density lipoproteins.)

Figure 27-1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of preference: (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase; FFA, free fatty acids; VLDL, very low density lipoproteins.)

Table 27-1. Energy yields, oxygen consumption, and carbon dioxide production in the oxidation of metabolic fuels.

Energy Yield (kJ/g)

O2 Consumed (L/g)

CO2 Produced (L/g)


Oxygen (kJ/L)



















hydrolyzed by glucose-6-phosphatase, and glucose is released into the blood stream for use by other tissues, particularly the brain and erythrocytes.

Muscle glycogen cannot contribute directly to plasma glucose, since muscle lacks glucose-6-phos-phatase, and the primary purpose of muscle glycogen is to provide a source of glucose 6-phosphate for energy-yielding metabolism in the muscle itself. However, acetyl-CoA formed by oxidation of fatty acids in muscle inhibits pyruvate dehydrogenase and leads to citrate accumulation, which in turn inhibits phosphofructoki-nase and therefore glycolysis, thus sparing glucose. Any accumulated pyruvate is transaminated to alanine at the expense of amino acids arising from breakdown of protein reserves. The alanine—and much of the keto acids resulting from this transamination—are exported from muscle and taken up by the liver, where the alanine is transaminated to yield pyruvate. The resultant amino acids are largely exported back to muscle to provide amino groups for formation of more alanine, while the pyruvate is a major substrate for gluconeogenesis in the liver.

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose.

Table 27-2. Plasma concentrations of metabolic fuels (mmol/L) in the fed and starving states.


40 Hours Starvation

7 Days Starvation





Free fatty acids




Ketone bodies




Although muscle takes up and preferentially oxidizes free fatty acids in the starving state, it cannot meet all of its energy requirements by P-oxidation. By contrast, the liver has a greater capacity for P-oxidation than it requires to meet its own energy needs and forms more acetyl-CoA than can be oxidized. This acetyl-CoA is used to synthesize ketone bodies (Chapter 22), which are major metabolic fuels for skeletal and heart muscle and can meet some of the brain's energy needs. In prolonged starvation, glucose may represent less than 10% of whole body energy-yielding metabolism. Furthermore, as a result of protein catabolism, an increasing number of amino acids are released and utilized in the liver and kidneys for gluconeogenesis.

Summary Metabolism Figure

Figure 27-2. Relative changes in metabolic parameters during the onset of starvation.

Table 27-3. Summary of the major and unique features of metabolism of the principal organs.


Major Function

Major Pathways

Main Substrates

Major Products

Specialist Enzymes


Service for the other organs and tissues

Most represented, including gluconeogenesis; P-oxidation; ketogenesis; lipoprotein formation; urea, uric acid, and bile acid formation; cholesterol synthesis; lipogenesis1

Free fatty acids, glucose (well fed), lactate, glycerol, fructose, amino acids


Glucose, VLDL (triacylglycerol), HDL, ketone bodies, urea, uric acid, bile acids, plasma proteins


Glucokinase, glucose-6-phosphatase, glycerol kinase, phosphoenolpyruvate carboxykinase, fructokinase, arginase, HMG-CoA synthase and lyase, 7a-hydroxylase

(Alcohol dehydrogenase)


Coordination of the nervous system

Glycolysis, amino acid metabolism

Glucose, amino acid, ketone bodies (in starvation) Polyunsaturated fatty acids in neonate



Pumping of blood

Aerobic pathways, eg, P-oxidation and citric acid cycle

Free fatty acids, lactate, ketone bodies, VLDL and chylo-micron triacylglycerol, some glucose

Lipoprotein lipase. Respiratory chain well developed.

Adipose tissue

Storage and breakdown of triacylglyc-erol

Esterification of fatty acids and lipolysis; lipogenesis1

Glucose, lipoprotein triacyl-glycerol

Free fatty acids, glycerol

Lipoprotein lipase, hormone-sensitive lipase

Muscle Fast twitch Slow twitch

Rapid movement Sustained movement


Aerobic pathways, eg, P-oxidation and citric acid cycle


Ketone bodies, triacylglycerol in VLDL and chylomicrons, free fatty acids


Lipoprotein lipase. Respiratory chain well developed.


Excretion and glu-coneogenesis


Free fatty acids, lactate, glycerol


Glycerol kinase, phosphoenolpyruvate carboxykinase


Transport of O2

Glycolysis, pentose phosphate pathway. No mitochondria and therefore no P-oxidation or citric acid cycle.




1In many species but not very active in humans.

1In many species but not very active in humans.

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    How many metabolic fuels are there?
    2 years ago
  • dennis
    How are the various metabolic fuels interconvertable?
    4 months ago

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