General Features Of Energy Metabolism

In discussing how hormones regulate fuel metabolism, we consider first the characteristics of metabolic fuels and the intrinsic biochemical regulatory mechanisms on which hormonal control is superimposed.

Body Fuels

Glucose

Glucose is readily oxidized by all cells. One gram yields about 4 Calories. The average 70-kg man requires approximately 2000 Calories per day and therefore would require a reserve supply of approximately 500 g of glucose to ensure sufficient substrate to survive 1 day of food deprivation. If glucose were stored as an isosmolar solution, approximately 10 L of water (10 kg) would be needed to accommodate a single day's energy needs, and the 70-kg man would have to carry around a storage depot equal to his own weight if he were to survive only 1 week of starvation. Actually, only about 20 g of free glucose is dissolved in extracellular fluids, or enough to provide energy for about 1 hr.

Glycogen

Polymerizing glucose to glycogen eliminates the osmotic requirement for large volumes of water. To meet a single day's energy needs, only about 1.8 kg of "wet" glycogen is required; that is, 500 g of glycogen obligates only about 1.3 L of water. Glycogen stores in the well fed 70-kg man are only enough to meet part of a day's energy needs—about 100 g in the liver and about 200 g in muscle.

Calories can also be stored in somewhat more concentrated form as protein. Storage of protein, however, also obligates storage of some water, and oxidation of protein creates unique by-products: ammonia, which must be detoxified to form urea at metabolic expense, and sulfur-containing acids. The body of a normal 70-kg man in nitrogen balance contains about 10-12 kg of protein, most of which is in skeletal muscle. Little or no protein is stored as an inert fuel depot, so that mobilization of protein for energy necessarily produces some functional deficits. Under conditions of prolonged starvation, as much as one-half of the body protein may be consumed for energy before death ensues, usually from failure of respiratory muscles.

Triglycerides are by far the most concentrated storage form of high-energy fuel (9 Calories/g), and they can be stored essentially without water. One day's energy needs can be met by less than 250 g of triglyceride. Thus a 70-kg man carrying 10 kg of fat maintains an adequate depot of fuel to meet energy needs for more than 40 days. Most fat is stored in adipose tissue, but other tissues such as muscle also contain small reserves of triglycerides.

Problems Inherent in the Use of Glucose and Fat as Metabolic Fuels

1. Fat is the most abundant and efficient energy reserve, but efficiency has its price. When converting dietary carbohydrate to fat, about 25% of the energy is dissipated as heat. More importantly, synthesis of fatty acids from glucose is an irreversible process. Once the carbons of glucose are converted to fatty acids, virtually none can be reconverted to glucose. The glycerol portion of triglycerides remains convertible to glucose, but glycerol represents only about 10% of the mass of triglyceride.

2. Limited water solubility of fat complicates transport between tissues. Triglycerides are "packaged" as very-low-density lipoproteins or as chylomicrons for transport in blood to storage sites. Uptake by cells follows breakdown to fatty acids by lipoprotein lipase at the external surface or within capillaries of muscle or fat cells. Mobilization of stored triglycerides also requires breakdown to fatty acids, which leave adipocytes in the form of free fatty acids (FFA). FFA are not very soluble in water and are transported in blood firmly bound to albumin. Because they are bound to albumin, FFA have limited access to tissues such as brain; they can be processed to water-soluble forms in the liver, however, which converts them to 4-carbon ketoacids (ketone bodies), which can cross the blood-brain barrier.

3. Energy can be derived from glucose without simultaneous consumption of oxygen, but oxygen is required for degradation of fat. Therefore, glucose must be constantly available in the blood to satisfy the needs of red blood cells, which lack mitochondria, and cells in the renal medullae, which function under low oxygen tension. Under basal conditions these cells consume about 50 g of glucose each day and release an equivalent amount of lactate into the blood. Because lactate is readily reconverted to glucose in the liver, however, these tissues do not act as a drain on carbohydrate reserves.

4. In a well-nourished person the brain relies almost exclusively on glucose to meet its energy needs and consumes nearly 150 g per day. Brain does not derive energy from oxidation of FFA or amino acids. Ketone bodies are the only alternative substrates to glucose, but studies in experimental animals indicate that only certain regions of the brain can substitute ketone bodies for glucose. Total fasting for 4-5 days is required before the concentrations of ketone bodies in blood are high enough to provide a significant fraction of the brain's energy needs. Even after several weeks of total starvation, the brain continues to satisfy about one-third of its energy needs with glucose. The brain stores little glycogen and hence must depend on the circulation to meet its minute-to-minute fuel requirements. The rate of glucose delivery depends on its concentration in arterial blood, the rate of blood flow, and the efficiency of extraction. Although an increased flow rate might compensate for decreased glucose concentration, the mechanisms that regulate blood flow in brain are responsive to oxygen and carbon dioxide, rather than glucose. Under basal conditions the concentration of glucose in arterial blood is about 5 mM (90 mg/dL), of which the brain extracts about 10%. The fraction extracted can double, or perhaps even triple, when the concentration of glucose is low; but when the blood glucose falls below about 30 mg/dL, metabolism and function are compromised. Thus the brain is exceedingly vulnerable to hypoglycemia, which can quickly produce coma or death.

Fuel Consumption

The amount of metabolic fuel consumed in a day varies widely and normally is balanced by variations in food intake, but the adipose tissue reservoir of triglycerides can shrink or expand to accommodate imbalances in fuel intake and expenditure. Muscle comprises about

FIGURE 1 Intraorgan flow of substrate and the competitive regulatory effects of glucose and fatty acids that comprise the glucose-fatty acid cycle. Dashed arrows denote inhibition. See text for details.

50% of body mass and is by far the major consumer of metabolic fuel. Even at rest muscle metabolism accounts for about 30% of the oxygen consumed. Although normally a 56-kg woman or a 70-kg man or consumes about 1600 or 2000 Calories in a typical day, daily caloric requirements may range from about 1000 with complete bed rest to as much as 6000 with prolonged physical activity. For example, marathon running may consume 3000 Calories in only 3 hr. Under basal conditions an individual on a typical mixed diet derives about half of the daily energy needs from the oxidation of glucose, a small fraction from consumption of protein, and the remainder from fat. With starvation or with prolonged exercise, limited carbohydrate reserves are quickly exhausted unless some restriction is placed on carbohydrate consumption by muscle, whose fuel needs far exceed those of any other tissue and can be met by increased utilization of fat. In fact, simply providing muscle with fat restricts its ability to consume carbohydrate. Hormonal regulation of energy balance is largely accomplished through adjusting the flux of energy-rich fatty acids and their derivatives to muscle, and the consequent sparing of carbohydrate and protein.

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