BIOCHEMISTRY AND MOLECULAR BIOLOGY - W. ELLIOTT - 2002

CHAPTER 5. AN INTRODUCTION TO THE DISTRIBUTION AND UTILIZATION OF ENERGY SOURCES IN VARIOUS BODY TISSUES

This chapter is dedicated to METABOLISM proper. First, we will examine the exchange of molecules between Blood and Tissues, as well as among different tissues. Next, we will discuss The regulatory mechanisms of these processes that meet the physiological needs of the Organism, with a focus on the allocation of Energy Sources among its consumers.

The primary task of metabolism is to supply the organism with energy stored as ATP through The oxidation of nutrients. Food molecules serve as raw Materials for building cellular components and Other Compounds essential for the body. Waste products, i.e., substances unnecessary to the organism, are converted into compounds that can be excreted in the urine. Some specialized Cells in newborns use the oxidation of nutrients to generate heat. Heat production is a byproduct of metabolism.

Energy Storage in the Animal Body

As is well known, animals ingest food at discrete intervals rather than continuously. Many of them exhibit cyclically recurring periods of feeding and fasting. In humans, meals may be separated by short intervals (during the day), longer breaks (during night Sleep), or significant periods (during fasting). Biochemical machinery must somehow adapt to these situations.

Immediately after a meal, the blood becomes rich in nutrients absorbed from the intestine. However, they do not remain there for long; instead, they rapidly pass into the tissues, so their concentration in the blood soon drops back to its previous low level. For example, after a fatty meal, lipemia develops (Blood Plasma takes on a milky appearance), but this condition resolves within a few hours. Postprandial blood glucose concentration rises from 5 to 7.8 mM within an hour, but returns to normal within two hours (in non-diabetic individuals). Although tissues rapidly take up nutrients from the blood, they do not use them immediately. The majority of the absorbed nutrients are stored as reserves.

How Are Various Types of Nutrients Stored in Cells?

Glucose Is Stored as Glycogen

It is impractical for cells to accumulate and store free glucose because the intracellular osmotic pressure would reach unacceptably high values. Recall that osmotic pressure is proportional to the molar concentration of the solute. However, if many individual dissolved molecules are combined into a single polymer, the accumulation of glucose will not lead to a noticeable increase in osmotic pressure. The resulting polymers do not always remain in solution; they may precipitate out as granules. In animals, glucose is polymerized into glycogen, or animal starch, which is structurally similar to amylopectin but features a higher degree of branching (see p. 76). The synthesis of glycogen requires an energy input. When needed, glycogen is broken down within The Cell to release glucose. It should be emphasized that animal glycogen reserves are extremely limited. For instance, in humans, glycogen is stored in the Liver, from which glucose generated by glycogen breakdown is delivered to other Organs and tissues. The entire glycogen reserve is depleted after a 24-hour fast. This circumstance is of fundamental importance for animal biochemistry.

As for other dietary Monosaccharides—galactose and fructose—they are converted in the body into glucose (or glycogen) or into compounds that act as glucose metabolites.

Fat Storage

The bulk of fats (triglycerides) is stored in adipose tissue or fat cells distributed throughout various PARTS OF THE body. Under the Microscope, these cells often appear as fat droplets bordered by a thin layer of Cytoplasm and a membrane (Fig. 5.1).

Class="center">Fig. 5.1. Fat cell (schematic)

Unlike glycogen, fats can be stored in the body in unlimited quantities. Under normal conditions, a human stores 50 times more energy as fat than as glycogen. What accounts for this ratio, especially considering the crucial metabolic role of glucose? Fats are much more reduced compounds than glucose; consequently, the oxidation of equal weights of fat and glucose yields significantly more energy in the first case. Thus, fats are the most compact form of energy storage. Paradoxically, we would look much fatter if our bodies accumulated glycogen instead of fat.

Since glucose is stored in small amounts while its dietary intake is quite high, the excess is converted into fat.

Glucose is readily converted into fats in the body, whereas no metabolic pathway exists for The conversion of Fatty acids into glucose. THE CONTRIBUTION OF glycerol to cellular energetics is incomparably smaller than that of long-chain fatty acids.

Are Amino Acids Stored in the Body?

Plant seeds contain Proteins whose sole function is to serve as a source of amino acids for the developing embryo. In animals, only egg and milk Proteins can be considered a form of amino acid storage. Dietary amino acids entering the animal bloodstream are utilized for the synthesis of proteins, Neurotransmitters, etc., while unused amino acids undergo degradation. In the process, the nitrogen derived from amino acids is incorporated into urea (a neutral, Water-soluble, and non-toxic compound) and excreted from the animal's body in the urine. Depending on its Structure, the nitrogen-free carbon Skeleton is converted into fats or glycogen, or oxidized to meet the organism's energy demands (Fig. 5.3).

Fig. 5.3. The Fate of dietary amino acids. The Selection of a metabolic pathway (a, b, or c) depends on amino acid structure, the physiological state of the organism, and regulatory mechanisms

At the same time, all cellular proteins can be viewed as a form of amino acid storage. This applies particularly to the contractile proteins of Muscle cells, which are degraded under conditions when the organism lacks dietary amino acids.

Energy Metabolism in Various Tissues

All body tissues differ in their biochemical characteristics. We will focus on those tissues that are of paramount importance for

distribution and utilization of nutrients. We will focus on the liver, skeletal Muscles, Brain, adipose cells, and erythrocytes. Regulatory organs such as the Pancreas and Adrenal Glands will not be discussed here.

1. The liver plays a central role in maintaining a constant blood glucose concentration. When blood glucose levels are high (following a meal), the excess is stored in the liver as glycogen. When the body demands it, hepatic glycogen is broken down, and glucose is released into the bloodstream.

When fasting lasts for more than a day, liver glycogen stores become depleted, and if left unchecked, blood glucose levels can drop to a life-threatening degree. In such cases, the body mobilizes fat reserves released into the bloodstream by adipose tissue cells. However, while these can sustain muscle and other tissues, they cannot support the brain and erythrocytes, which rely exclusively on glucose and cannot metabolize fatty acids. The liver solves this problem by converting amino acids into glucose—a process known as Gluconeogenesis. The primary source of amino acids for this pathway is The breakdown of Muscle Proteins. Naturally, the muscles suffer, but this is still preferable to death from glucose deprivation.

The liver plays an equally vital role in Lipid Metabolism. When prolonged fasting triggers the release of fatty acids into the blood, they are utilized by all tissues (except the brain and erythrocytes). If fat mobilization becomes substantial, the liver converts fatty acids into compounds called Ketone Bodies. These enter the bloodstream and are also utilized by tissues (excluding erythrocytes). Ketone bodies can supply up to half of the brain's Energy Requirements, thereby reducing its dependence on glucose. In addition to breaking down fatty acids, the liver can also synthesize them, after which they are transported to other tissues as triglycerides.

Thus, the liver stores glucose as glycogen and releases it when needed, provided glycogen reserves are not exhausted. During fasting, it converts amino acids into glucose and fats into ketone bodies, supplying other tissues via the bloodstream (Fig. 5.4). Beyond synthesizing and exporting fatty acids, the liver can also oxidize them for energy. And these are only the hepatic Functions directly related to the body's energy supply.

Fig. 5.4. Pathways of biological fuel in a fasting organism

2. The brain lacks its own energy reserves and requires a continuous supply of glucose. Glucose Transport into Neurons is passive and therefore ceases if blood glucose concentrations drop (hypoglycemia), leading to seizures and coma. Nevertheless, while glucose is absolutely essential for brain function, the brain can meet up to half of its energy demands using ketone bodies, thus conserving glucose for situations where it is indispensable.

3. Skeletal muscles consume large amounts of energy during contraction, drawing it from various sources. Muscles absorb glucose from the blood and can store it as glycogen. Unlike the liver, however, glucose released from muscle glycogen does not enter the bloodstream. In addition to glucose, muscles oxidize fatty acids, ketone bodies, and amino acids. Moreover, when blood levels of Fatty Acids and ketones are sufficiently high, they become the primary substrates for oxidation. During fasting, muscles "sacrifice" their proteins to supply the liver with amino acids for gluconeogenesis.

4. The Role of adipose cells is relatively straightforward. Following a meal, they absorb fatty acids and glucose from the bloodstream and convert these substances into triglycerides.

Conversely, when a drop in blood glucose signals a state of fasting, fat cells draw upon their triglyceride reserves to release fatty acids into the blood, meeting the metabolic needs of other tissues. Adipose cells and the liver are the primary producers of triglycerides. Fatty acids are either obtained from the diet or synthesized in the liver, while glycerol is derived from glucose.

5. Erythrocytes can only utilize glucose, converting it into lactic acid. Lacking Mitochondria, they are unable to oxidize nutrients like other cells do. Consequently, glucose satisfies all of their energy requirements, including The activity of Na⁺/K⁺-ATPase.

The Role of Hormones in Coordinating Nutrient Distribution

Having examined the roles of individual organs and tissues in nutrient utilization, it is helpful to discuss how their activities are coordinated to enable the body to cope with various physiological states. The most typical of these are outlined below.

1. Nutrient surplus following a hearty meal.

2. Mild fasting after a short interval between meals, such as in the morning before breakfast.

3. Fasting—a state occurring after a food deprivation of one to two days.

4. Pathological conditions (e.g., diabetes, where glucose is not cleared from the bloodstream).

5. Extreme stress (where a massive surge of adrenaline is released into the blood).

The Postabsorptive State

All dietary components are present in the blood at significant concentrations. Glucose is taken up by the liver, muscles, and adipose cells and used to replenish glycogen stores. Additionally, some glucose is converted into neutral fats within the liver, adipose tissue, and other tissues.

The liver itself does not accumulate synthesized fats in large amounts, exporting them to other tissues instead (fatty liver is a pathological condition).

Amino acids are absorbed by all tissues and utilized for the synthesis of proteins and other cellular components. Lipids are derived from chylomicrons and taken up by

various tissues, including adipose cells for storage and mammary gland cells for milk production. During periods of glycogen and fat accumulation, the breakdown of these substances within cells does not occur.

The primary signal prompting all body tissues to shift into storage mode is the pancreatic hormone Insulin. Its release into the bloodstream informs all cells of an elevated glucose concentration, signaling a favorable environment for glycogen and fat synthesis. At the same time, high blood glucose leads to a decrease in the level of another pancreatic hormone, Glucagon, which exerts the opposite effect of insulin. Glucagon alerts cells to a nutrient shortage and prompts them to mobilize stored reserves: glycogen and neutral fats. Notably, the brain is insensitive to insulin; it relies entirely on a continuous supply of glucose.

Mild Hunger

Insulin-stimulated storage leads to a gradual decrease in blood levels of glucose, amino acids, and fats in the form of chylomicrons. In parallel with the drop in glucose concentration, insulin secretion also declines. This protein hormone is rapidly degraded in the bloodstream by proteinases, so the inhibition of its secretion leads to its nearly complete disappearance from the blood. On the other hand, the decrease in glucose concentration prompts the pancreas to secrete glucagon. This hormone signals The Liver and fat cells to mobilize glycogen and fat reserves to ensure a steady supply of glucose and fatty acids to the bloodstream. The latter are used as fuel by muscles, the liver, and other tissues, sparing glucose for the needs of the brain. At the same time, low insulin levels combined with high glucagon levels suppress the synthesis of glycogen and fats from glucose.

Prolonged Fasting

As early as one day of fasting, liver glycogen stores are depleted, and the liver can no longer maintain adequate blood glucose levels (glycogen in the Kidneys lasts a bit longer, but their contribution to this process is negligible). Insulin levels are low, while glucagon levels are high. Under these conditions, fat cells begin releasing fatty acids into the blood, which become the primary energy source for tissues. The fat reserves in these cells can last for more than a

week. In muscles, proteins break down into amino acids, from which the liver synthesizes glucose under The Influence of glucagon. As fasting continues, glucagon increasingly stimulates fat cells to raise fatty acid levels in the blood, and the liver activates the pathway for ketone body formation. This long-used and misleading term refers to two compounds: acetoacetate (СН₃СОСН₂СОО^-) and β-hydroxybutyrate (СН₃СНОНСН₂СОО^-). The second substance is not a ketone, and neither of them are "bodies." It was previously believed that the presence of ketone bodies indicated pathological conditions, but in reality, their synthesis occurs as part of normal metabolism.

Diabetes

In the absence of insulin, muscles cannot utilize glucose, no matter how abundant it is in the blood. This is precisely the case in diabetics, whose lives are saved solely by the fact that the brain and red Blood Cells absorb glucose independently of insulin action. The metabolic state in diabetes resembles prolonged fasting, where the insulin-to-glucagon concentration ratio is extremely low, and fat cells produce large amounts of fatty acids, some of which the liver converts into ketone bodies. The concentration of the latter becomes significantly higher than normal, which is easily detected by a characteristic sweetish "organic" breath odor. This is the scent of acetone, which arises through the spontaneous decarboxylation of acetoacetate:

СН₃СОСН₂СОО^- —> СН₃СОСН₃ + СO₂.

Emergency Situation

When a person is in danger, their adrenal glands, obeying a nerve signal from the brain, release adrenaline into the bloodstream. Adipose tissue is innervated, and its activity is likewise stimulated by adrenaline released from nerve endings. Adrenaline acts on the body much like pressing an "Alarm!" button. It prompts the liver and fat cells to release glucose and fatty acids into the blood in quantities sufficient to ensure that muscles do not lack "fuel." In addition, it triggers the breakdown of glycogen within the muscles themselves so that their cells can produce ATP at maximum speed. Together, these measures put the muscles into a working state that allows their owner to escape danger.

Questions for Chapter 5

1. Why do cells store glucose as glycogen?

2. Why are triglycerides stored in much greater quantities than glycogen?

3. Can glucose be converted into fats in the body and vice versa? Are there any special storage forms for amino acids?

4. Describe the role of the liver in nutrient Processing and distribution.

5. Does the brain use fatty acids as an energy source?

6. List the main metabolic properties of fat cells.

7. What serves as the energy source in red blood cells?

8. Which hormones bear primary responsibility for nutrient utilization?