Pupule puhi ahi.

Crazy person who sets fires.

A humorous expression applied to one with an overabundance of energy who does as he pleases without fear of being criticized. Such a person has so much generosity that he is likable, even if he sometimes goes to extremes.

ʻŌlelo Noʻeau, compiled by Mary Kawena Pukui, #2760

Introduction

In Hawaiʻi, we love to eat. Eating is essential to life, and you most likely have heard about the importance of a balanced diet, with plenty of fruits and vegetables. But what does this all mean to your body and the physiological processes it carries out each day? This chapter will take you through some of the chemical reactions essential to life, the sum of which is referred to as metabolism. Metabolism varies, depending on age, gender, genetics, activity level, fuel consumption, and body mass. Aging is known to decrease the metabolic rate by as much as five percent per year. Because men tend to have more muscle mass than women, their basal metabolic rate (the metabolic rate at rest) is higher, and therefore, men tend to burn more calories. Additionally, an individual’s inherent metabolic rate depends on the proteins and enzymes derived from their genetic background. Thus, your genes play a big role in your metabolism. By modifying your diet and exercise regimen, you can change your metabolic rate. Nonetheless, each person’s body engages in the same overall metabolic processes.

24.1 Overview of the Metabolic Reactions

Metabolic processes are constantly taking place in the body. Metabolism is the sum of all the chemical reactions that are involved, and we can see a glimpse of what is going on in the cells from the following partial map of the human metabolic pathways. These reactions are catalyzed by enzymes and proteins of the body that speed up biochemical reactions.

Figure 24.2 Partial Map of the Human Metabolic Pathway. This image depicts a partial map of the human metabolic pathways. (By Evans Love  —  Own work, CC BY-SA 4.0, Wiki ).

Enzymes

Enzymes catalyze the rate of biochemical reactions within the body by binding substrates and turning them into products. Most enzymes are proteins with a complex 3D structure containing an active site that fits and binds other molecules (the substrates). For the enzyme to convert a substrate into a product, input energy known as activation energy is required. Chemical reactions may release or absorb energy. Reactions that release energy are called exergonic, those that absorb energy are called endergonic reactions. Some reactions may be reversible, while others require such a large amount of activation energy they are practically irreversible.

Figure 24.3 Exergonic vs endergonic reaction: Exergonic and endergonic reactions result in changes in Gibbs free energy (G). Exergonic reactions have a net release of energy and are spontaneous reactions. Endergonic reactions require an input of energy to proceed and are nonspontaneous reactions. Both Exergonic and endergonic reactions require initial activation energy for the reaction to occur. Credit: Tag, A., Rao, A., Fletcher, S. and Ryan, A. Department of Biology, Texas A&M University.

Figure 24.4: Reversible reactions (a) A sealed tube containing colorless N₂O₄ darkens as it decomposes to yield brown NO₂. (b) Changes in concentration over time as the decomposition reaction achieves equilibrium. (c) At equilibrium, the forward and reverse reaction rates are equal.

Spontaneous heat flow from an object at higher temperature 𝑇2 ${}_{\mathrm{}}$ to another at lower temperature 𝑇1.	A gas expanding from half of a container to the entire container (a) before and (b) after the wall in the middle is removed.

Figure 24.5: Irreversible Processes

The active site of enzymes is very specific to the shape of the molecule that they bind. In other words, they will not bind other molecules that do not fit a specific shape. You can imagine the enzyme and the substrate work similarly like a lock and a key. Only a specific set of keys can open a certain lock. Therefore, it is often described as a lock-and-key mechanism. In addition to the activation energy, some enzymes also require cofactors, an additional atom or molecule needed for the enzyme to bind its substrate. Besides cofactors, temperature, salt concentration, and pH can alter the shape of proteins and therefore change the substrate-binding site. This may cause reactions to speed up or slow down, depending on the enzyme. Substrate concentration can also influence enzyme performance. Enzyme-specific chemical inhibitors may influence the rate of enzyme catalysis. There are competitive inhibitors that occupy or block the active site on an enzyme and allosteric inhibitors that bind the enzyme away from the active site but still alter the protein shape.

Figure 24.6 Enzyme-Substrate Complex Enzyme changes shape by induced fit upon substrate binding to form enzyme-substrate complex. Hexokinase has a large induced fit motion that closes over the substrates adenosine triphosphate (ATP) and xylose. Binding sites in blue, substrates in black and Mg2+ cofactor in yellow. (By Thomas Shafee – Own work, CC BY 4.0, Wiki)

Competitive Inhibition	Non-competitive Inhibition

Figure 24.7: Competitive and Allosteric Inhibitions Molecules that are competitive inhibitors of enzymes resemble one of the normal substrates of an enzyme. Allosteric inhibitors do not resemble the substrate and bind not to the active site, but rather to a separate site on the enzyme. (LibreText)

Enzymes work in conjunction with other enzymes to produce complex metabolic pathways which allow our bodies to convert one type of molecule into others. These groups of enzymes can be arranged in a cascade or as multienzyme complexes. Regulation usually occurs at one critical step whereby turning off one enzyme halts the entire pathway. One common method of turning enzymes on or off is the addition or removal of phosphate groups.

Catabolic vs Anabolic Reactions

Enzymatic reactions can be generally classified as either catabolic or anabolic. Catabolic reactions break down large organic molecules into smaller molecules, releasing the energy contained in the chemical bonds. In contrast, anabolic reactions involve the joining of smaller molecules into larger ones. Anabolic reactions combine monosaccharides to form polysaccharides, fatty acids to form triglycerides, amino acids to form proteins, and nucleotides to form nucleic acids. In summary, catabolic reactions involve breaking down substances and releasing energy whereas anabolic reactions involve building up substances and require energy.

There are several major classes of enzymes. Oxidoreductases transfer electrons from one substance to another. Transferases move a functional group between molecules. One specific type of transferase is a kinase which transfers phosphate groups. Hydrolases split large molecules using water. A phosphatase is a specific hydrolase enzyme that removes a phosphate group by breaking a chemical bond using water. Ligases ligate (bind) two smaller molecules, whereas lyases split molecules. Isomerases rearrange molecules without adding or removing any atoms, hence the “iso” prefix. Usually, the enzyme prefixes give a good hint about the action of the enzyme with the “-ase” suffix. For example, a hexokinase is an enzyme that phosphorylates (kinase) a hexose (a six-carbon sugar).

The Role of ATP

Cells are small and they cannot use macromolecules such as polysaccharides and lipids directly for energy; instead, these nutrients must be broken down into monomers, and the energy released is used to form ATP (Figure 24.7). ATP is a molecule that is used by all cells as energy to perform work. When enzymes break chemical bonds, some of the energy can be used to form the energy transfer molecule adenosine triphosphate (ATP). ATP, the energy currency inside cells, is used to power biochemical reactions by breaking chemical bonds and releasing energy. Structurally, ATP molecules consist of an adenine, a ribose, and three phosphate groups (Figure 24.7). The chemical bond between the second and third phosphate groups breaks, releasing energy and forming ADP and a free phosphate group. Sometimes ADP can also be used for extra energy by an enzyme breaking the bond between the first and second phosphate groups forming AMP. A similar molecule used in some enzymatic reactions is called GTP.

Figure 24.7 Sources of ATP: During catabolic reactions, proteins are broken down into amino acids, lipids are broken down into fatty acids, and polysaccharides are broken down into monosaccharides. These building blocks are then used for the synthesis of molecules in anabolic reactions. (OpenStax A&P)

Figure 24.8 Structure of ATP Molecule: Adenosine triphosphate (ATP) is the energy molecule of the cell. In catabolic reactions, ATP is created, and energy is stored until needed during anabolic reactions. The energy from ATP drives all bodily functions, such as contracting muscles, maintaining the electrical potential of nerve cells, and absorbing food in the gastrointestinal tract. The metabolic reactions that produce ATP come from various sources. (OpenStax A&P)

Macromolecules

The body uses four major macromolecule groups (carbohydrates, lipids, proteins, and nucleic acids) to generate ATP. These are processed by mechanical and chemical digestions into monomer molecules that can be readily absorbed in the GI tract. Carbohydrates are consumed as complex carbohydrates, polysaccharides like starch and glycogen, or simple sugars (monosaccharides) like glucose and fructose. Simple sugars are absorbed without enzyme involvement. However, large polysaccharides must first be broken down into their individual monosaccharides. Among the monosaccharides, glucose is the most common fuel for ATP production in cells and, as such, is often used initially to explain metabolic processes.

Storage

Excess nutrients are stored in the body as an energy reserve. Glucose is either stored in the liver and skeletal muscles as the complex polymer glycogen or is converted to fat (triglyceride) in adipocytes. Triglycerides are the most common lipids used for ATP production and are broken down via a metabolic process called β-oxidation. Excess fat is stored in adipocytes that accumulate in the subcutaneous tissue under the skin or other tissues and organs. Proteins, which are polymers of amino acid monomers, can be broken down and used as building blocks to make a variety of proteins such as enzymes and transporters. Nucleic acids are present in most of the foods you eat. During digestion, nucleic acids, including DNA and various RNAs, are broken down into their constituent nucleotides. These nucleotides are readily absorbed and transported throughout the body to be used as building blocks for making other molecules, including your DNA or RNA. Besides making new proteins and nucleic acids, amino acids and nucleotides are not converted to triglycerides within adipocytes like carbohydrates and lipids.

Hormonal Regulation of Metabolism

Catabolic and anabolic hormones in the body help regulate metabolic processes. Catabolic hormones stimulate the breakdown of molecules and the production of energy. These include cortisol, glucagon, adrenaline (epinephrine), and some cytokines. Anabolic hormones stimulate the synthesis of molecules which include growth hormone (GH), insulin-like growth factor (IGF), insulin, testosterone, and estrogen. Table 24.1 summarizes the function of each of the catabolic hormones, and Table 24.2 summarizes the functions of the anabolic hormones.

Table 24.1 Catabolic Hormones

Table 24.2 Anabolic Hormones

Oxidation-Reduction Reactions

Many chemical reactions underlying metabolism involve the transfer of electrons from one compound to another. The electrons in these reactions commonly come from hydrogen atoms, consisting of an electron and a proton. The loss of an electron, or oxidation, releases a small amount of energy; both the electron and the energy are then passed to another molecule in the process of reduction or the gaining of an electron. These two reactions always happen together in what is called an oxidation-reduction reaction (also called a redox reaction). When an electron is passed between molecules, the donor is oxidized and the recipient is reduced. Oxidation-reduction reactions often happen in a series, so that a molecule that is reduced is subsequently oxidized, passing on not only the electron but also the energy it received. Oxidation-reduction reactions are catalyzed by enzymes that trigger the removal of hydrogen atoms. Coenzymes often accept these hydrogen atoms and electrons. Two common coenzymes of oxidation-reduction reactions are nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). When NAD is reduced it becomes NADH, and when FAD is reduced it becomes FADH2. Reduced molecules, such as NADH, have more energy than their oxidized counterparts because of the extra electron and chemical bond. In our cells, the electron transport chain is the location where these extra electrons will be extracted for the generation of cellular energy.

Figure 24.9 Structures of NAD/NADH (top) and FAD/FADH2 (bottom). (Wikipedia: By Fvasconcellos 19:44, 9 December 2007 (UTC). w:Image:NAD oxidation reduction.png by Tim Vickers. – Vector version of w:Image:NAD oxidation reduction.png by Tim Vickers., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3204642) (By DMacks – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2285012)

24.2 Carbohydrate Metabolism

To improve comprehension, it would help to review the structure of an atom. Recall that electrons surround the atom nucleus in shells or orbits. These electrons are lost, gained, or shared in processes called chemical reactions. In some chemical reactions, energy is released which can be harnessed to make ATP. In this section, the metabolism of glucose is reviewed through the process of Glycolysis, Krebs Cycle, and the Electron Transport Chain.

Overview of Glycolysis, Krebs Cycle, and Electron Transport Chain

Recall that carbohydrates are organic molecules composed of carbon, hydrogen, and oxygen atoms. The family of carbohydrates includes both simple and complex sugars. Glucose and fructose are examples of simple sugars whereas starch, glycogen, and cellulose are all examples of complex sugars. The complex sugars are also called polysaccharides and are made of multiple monosaccharide molecules.

During digestion, carbohydrates are ultimately broken down into simple, soluble sugars that can be transported across the intestinal wall into the circulatory system. Carbohydrate digestion begins in the mouth with the action of salivary amylase on starches and ultimately ends with monosaccharides being absorbed across the epithelium of the small intestine. Hepatocytes in the liver can pass the glucose on through the circulatory system or store excess glucose as glycogen. Cells in the rest of the body take up the circulating glucose in response to insulin. Once absorbed, monosaccharides are transported to the tissues where cellular respiration begins.

Glucose in the Fischer projection, (Wiki)	Glucose in the Haworth projection (Wiki)

Figure 24.10 Structures of Glucose Glucose is sugar with the molecular formula of C₆H₁₂O₆ and it contains six carbon atoms.

Figure 24.11 Cellular Respiration Cellular respiration oxidizes glucose molecules through glycolysis, the Krebs cycle, and oxidative phosphorylation to produce ATP.

Glycolysis

Once the glucose enters the cells, they will be guided towards a pathway known as glycolysis to extract its energy. Ultimately, glycolysis (Figure 24.10) splits glucose (a six-carbon sugar) to form two molecules of pyruvate (a three-carbon molecule). Glycolysis initially uses two ATPs but ultimately generates four ATPs, thus yielding a net gain of two ATPs. In the presence of oxygen, pyruvate continues through an intermediate stage and the Krebs cycle (also called the citric acid cycle or tricarboxylic acid cycle (TCA), where additional energy is extracted and passed on.

Figure 24.12 Glycolysis Overview: During the energy-consuming phase of glycolysis, two ATPs are consumed, transferring two phosphates to the glucose molecule. The glucose molecule then splits into two three-carbon compounds, each containing a phosphate. During the second phase, an additional phosphate is added to each of the three-carbon compounds. The energy for this endergonic reaction is provided by the removal (oxidation) of two electrons from each three-carbon compound. During the energy-releasing phase, the phosphates are removed from both three-carbon compounds and used to produce four ATP molecules.

Glycolysis can be divided into two phases: energy-consuming (also called chemical priming) and energy-yielding. The first phase is the energy-consuming phase, so it requires two ATP molecules to start the reaction for each molecule of glucose. However, the end of the reaction produces four ATPs, resulting in a net gain of two ATP energy molecules.

When glucose first enters a cell, the enzyme hexokinase rapidly adds a phosphate to convert it into glucose-6-phosphate. This conversion step requires one ATP and essentially traps the glucose in the cell, preventing it from passing back through the plasma membrane, thus allowing glycolysis to proceed. It also maintains a concentration gradient with higher glucose levels in the blood than in the tissues. By establishing this concentration gradient, the glucose in the blood will be able to flow from an area of high concentration (the blood) into an area of low concentration (the tissues) to be either used or stored.

In the next step, the enzyme glucose-6-phosphate isomerase converts glucose-6-phosphate into fructose-6-phosphate. Like glucose, fructose is also a six-carbon sugar. The enzyme phosphofructokinase-1 then adds one more phosphate to convert fructose-6-phosphate into fructose-1-6-bisphosphate, another six-carbon sugar, using another ATP molecule. Aldolase then breaks down this fructose-1-6-bisphosphate into two three-carbon molecules, glyceraldehyde-3-phosphate, and dihydroxyacetone phosphate. The triosephosphate isomerase enzyme then converts dihydroxyacetone phosphate into a second glyceraldehyde-3-phosphate molecule. Therefore, by the end of this chemical-priming or energy-consuming phase, one glucose molecule is broken down into two glyceraldehyde-3-phosphate molecules.

The second phase of glycolysis is the energy-yielding phase. Glyceraldehyde-3-phosphate dehydrogenase converts each three-carbon glyceraldehyde-3-phosphate into 1,3-bisphosphoglycerate. This reaction releases an electron that is then picked up by NAD+ to create an NADH molecule. Because there are two glyceraldehyde-3-phosphate molecules, two NADH molecules are synthesized during this step. Each 1,3-bisphosphoglycerate is subsequently dephosphorylated (i.e., a phosphate is removed) by phosphoglycerate kinase into 3-phosphoglycerate. Each phosphate released in this reaction can convert one molecule of ADP into one high-energy ATP molecule, resulting in a gain of two ATP molecules.

The enzyme phosphoglycerate mutase then converts the 3-phosphoglycerate molecules into 2-phosphoglycerate. The enolase enzyme then acts upon the 2-phosphoglycerate molecules to convert them into phosphoenolpyruvate molecules which are high-energy compounds. The last step of glycolysis involves the dephosphorylation of the two phosphoenolpyruvate molecules by pyruvate kinase to create two pyruvate molecules and two additional ATP molecules. In summary, glycolysis breaks down each glucose molecule into two pyruvate molecules, generating two ATP and two NADH molecules in the process.

Overall, glycolysis can be expressed as the following equation:

Glucose + 2 ATP + 2 NAD++ 4 ADP + 2Pi

→

2 Pyruvate + 4 ATP + 2 NADH + 2H+

This equation states that glucose, in combination with ATP (the energy source), NAD+ (a coenzyme that serves as an electron acceptor), and inorganic phosphate, breaks down into two pyruvate molecules, generating four ATP molecules—for a net yield of two ATP—and two energy-containing NADH coenzymes. The NADH that is produced in this process serves as an electron carrier and will be used later to produce ATP in the mitochondria. Importantly, by the end of this process, one glucose molecule generates two pyruvate molecules, two high-energy ATP molecules, and two electron-carrying NADH molecules.

Anaerobic Respiration

When oxygen is limited or absent, pyruvate enters an anaerobic pathway called fermentation. In these reactions, pyruvate can be converted into lactic acid. In addition to generating an additional ATP, this pathway keeps the pyruvate concentration low, so glycolysis continues. Fermentation processes also oxidize NADH into NAD+, further promoting the glycolysis pathway. Anaerobic respiration occurs in most body cells when oxygen is limited, or mitochondria are absent or non-functional. For example, because mature erythrocytes (red blood cells) lack mitochondria, they must produce their ATP from anaerobic respiration. The lactic acid produced diffuses into the plasma and is carried to the liver, where it is converted back into pyruvate or glucose via the Cori cycle. Similarly, when a person exercises at high intensities, muscles use ATP faster than oxygen can be delivered. They depend on glycolysis and lactic acid for rapid ATP production. The Cori cycle requires more ATP input than what was gained through glycolysis. Thus, anaerobic respiration provides immediate, fast energy but with net energy debt. This pathway of ATP production is effective only for short periods, ranging from seconds to a few minutes.

Figure 24.13 Aerobic versus Anaerobic Respiration: The process of anaerobic respiration converts glucose into two lactate molecules in the absence of oxygen or within erythrocytes that lack mitochondria. During aerobic respiration, glucose is oxidized into two pyruvate molecules.

The Krebs Cycle

Figure 24.14 Krebs Cycle: During the Krebs cycle, each pyruvate that is generated by glycolysis is converted into a two-carbon acetyl CoA molecule. The acetyl CoA is systematically processed through the cycle and produces high-energy NADH, FADH2, and ATP molecules.

Aerobic Respiration

In the presence of oxygen, the pyruvate molecules generated during glycolysis are transported across the mitochondrial membrane into the mitochondrial matrix, where they are further metabolized in a pathway called the intermediate stage. Here, pyruvate is converted by the enzyme pyruvate dehydrogenase into a two-carbon acetyl coenzyme A (acetyl CoA) molecule. This reaction is an oxidative decarboxylation reaction. It converts the three-carbon pyruvate into a two-carbon acetyl CoA molecule, releasing carbon dioxide and transferring two electrons that combine with NAD+ to form NADH.

Acetyl CoA then enters the Krebs cycle. Initially, citrate synthase combines acetyl CoA and oxaloacetate to form a six-carbon citrate molecule. The aconitase enzyme converts citrate into isocitrate. Thereafter, two successive steps of oxidative decarboxylation occur, generating two CO2 and two NADH molecules. Isocitrate dehydrogenase converts isocitrate into the five-carbon α-ketoglutarate, which is then catalyzed and converted into the four-carbon succinyl CoA by α-ketoglutarate dehydrogenase. The enzyme succinyl CoA dehydrogenase then converts succinyl CoA into succinate. This step also forms a GTP molecule, which subsequently transfers a phosphate group to ADP producing ATP. Succinate dehydrogenase then converts succinate to fumarate, forming a molecule of FADH2. Fumarase then converts fumarate into malate. From this, malate dehydrogenase then regenerates oxaloacetate and another NADH, thus completing the cycle. Oxaloacetate is then ready to combine with the next acetyl CoA to start the Krebs cycle again (see Figure 24.12). For each cycle, three NADH, one ATP (through GTP), and one FADH2 are created. Each carbon of pyruvate is converted into CO2, which is released as a waste product of oxidative (aerobic) respiration.

Oxidative Phosphorylation and the Electron Transport Chain

While some ATP is generated in glycolysis and the Kreb’s cycle, most of the body’s ATP is produced in the mitochondria which are the power plants of the cell. You recall that the mitochondrion contains two membranes: the outer and inner mitochondrial membranes.

Figure 24.15 Structure of a Mitochondrion Structure of a mitochondrion with an outer membrane, intermembrane space, and an inner membrane. (By Kelvinsong; modified by Sowlos  —  Own work based on: Mitochondrion mini.svg, CC BY-SA 3.0, Wiki)

The electron transport chain (ETC) is located on the inner mitochondrial membrane. The ETC consists of a series of four enzyme complexes (Complex I – Complex IV) and two coenzymes (ubiquinone and Cytochrome c), which act as electron carriers and proton (H+) pumps (Figure 24.8). The NADH and FADH2 are the electron carriers where they will be passing the electrons into the enzyme complexes for energy generation. For instance, NADH molecules pass electrons and H+ to Complex I, whereas FADH2 drops these off to Complex II. In a stepwise fashion, these complexes pass the electrons to adjacent complexes. Each passing of electrons releases a small amount of energy, which is used to pump H+ ions from the mitochondrial matrix into the intermembrane space between the outer and the inner mitochondrial membranes. The accumulation of these protons (H+) in the intermembrane space creates a higher proton gradient when compared to those inside the mitochondrial matrix. You can imagine this process as pumping or storing more water into the water dam which can be used to generate energy. In this case, the H+ ions are being stored in the intermembrane space and they can be used towards generating energy.

The last complex of the ETC that is embedded in the inner mitochondrial membrane is an enzyme called ATP synthase. As its name implies, this is an enzyme that synthesizes ATP. To do so, it allows H+ ions to cross the ATP synthase from the intermembrane space to the mitochondrial matrix. As H+ ions flow from high to low concentration into the mitochondrial matrix, the shaft of ATP synthase rotates. This rotation force produces mechanical energy to make ATP from ADP and Pi.

The ETC could not proceed without molecular oxygen O2, as it is the terminal electron acceptor. This means that electrons must be passed off to O2 for the ETC to continue. These electrons, O2, and the H+ ions combine to form metabolic water molecules, a byproduct of metabolism.

Figure 24.16 Electron Transport Chain The electron transport chain is a series of electron carriers and ion pumps that are used to pump H+ ions out of the mitochondrial matrix into the intermembrane space.

In summary, glycolysis produces a net gain of two ATP (four produced and two consumed during the energy-consuming stage). However, these two ATP are used for transporting the NADH produced during glycolysis from the cytoplasm into the mitochondria. Therefore, the real net production of ATP during glycolysis can be considered zero for those entering aerobic respiration. In all phases after glycolysis, the number of ATP, NADH, and FADH2 produced must be multiplied by two to reflect how each glucose molecule produces two pyruvate molecules. In the ETC, about three ATP are produced for every oxidized NADH. However, only about two ATP are produced for every oxidized FADH2. The electrons from FADH2 produce less ATP, because they start at a later point in the ETC through Complex II when compared to the electrons from NADH that enter through Complex I (see Figure 24.16). Therefore, for every glucose molecule that enters aerobic respiration, a net total of about 36 ATPs are produced (Figure 24.17).

Figure 24.17 Carbohydrate Metabolism: Carbohydrate metabolism involves glycolysis, the Krebs cycle, and the electron transport chain. (OpenStax A&P Textbook: Carbohydrate Metabolism)

Gluconeogenesis

Gluconeogenesis is the synthesis of new glucose molecules from pyruvate, lactate, glycerol, or amino acids (alanine or glutamine). This process occurs primarily in the liver during periods of low blood glucose, that is, under conditions of fasting, starvation, and low carbohydrate diets. Why does the body create something it constantly breaks down? Certain vital organs, including the brain, rely on glucose as their energy source. Gluconeogenesis ensures the needed blood glucose concentration to maintain these organs. When the blood glucose concentration falls below a certain point, new glucose is synthesized by the liver to raise the blood concentration to normal.

Gluconeogenesis is not simply the reverse of glycolysis, as there are some significant differences (Figure 24.18). Pyruvate is a common starting material for gluconeogenesis. First, the pyruvate is converted into oxaloacetate. Oxaloacetate then serves as a substrate for the enzyme phosphoenolpyruvate carboxykinase (PEPCK), transforming oxaloacetate to phosphoenolpyruvate (PEP). From this step, gluconeogenesis is nearly the reverse of glycolysis. PEP is converted back into 2-phosphoglycerate, 3-phosphoglycerate, 1,3 bisphosphoglycerate, and then glyceraldehyde-3-phosphate. The two molecules of the glyceraldehyde-3-phosphate combine to form fructose-1-6-bisphosphate, which is converted into fructose 6-phosphate and then into glucose-6-phosphate. Finally, a series of reactions generates glucose itself. In gluconeogenesis (as compared to glycolysis), the enzyme hexokinase is replaced by glucose-6-phosphatase, and the enzyme phosphofructokinase-1 is replaced by fructose-1,6-bisphosphatase. This helps the cell to regulate glycolysis and gluconeogenesis independently of each other.

Figure 24.18 Gluconeogenesis: Gluconeogenesis is the synthesis of glucose from pyruvate, lactate, glycerol, alanine, or glutamate.

Glycogenesis vs Glycogenolysis

In addition to generating new glucose molecules to maintain blood sugar levels, our bodies can also store excess glucose molecules in the form of glycogen. Glycogen is a polymer made from glucose and is primarily formed in the liver and skeletal muscles. These organs store the extra glucose so it can be released when it is needed. The process of making glycogen is called glycogenesis. The process of breaking down glycogen is called glycogenolysis.

Figure 24.19 Schematic Two-Dimensional Cross-Sectional View of Glycogen. A core protein of glycogenin is surrounded by branches of glucose units. The entire globular granule may contain around 30,000 glucose units. (Wikipedia: By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436.)

24.3 Lipid Metabolism

Lipids

When thinking about lipids or fats, we tend to have a negative oily image about them. Although high levels of lipids are indeed linked to diseases, lipids play a vital role in carrying out a diverse range of body functions. In this section, we will take a closer look at the story of lipids and how they are being transported and metabolized as fuels.

Lipid is the general term that includes fatty acids, triglycerides (fats), phospholipids, steroids (cholesterol, bile salts, and some hormones), eicosanoids, lipid-soluble vitamins, and lipoproteins. Most lipids within the body are ingested as food or synthesized by adipocytes or hepatocytes from carbohydrate precursors. Since most of them are made of carbon, hydrogen, and oxygen atoms, they have nonpolar characteristics. As a result, lipids are hydrophobic and do not mix well with water. However, they work perfectly as the essential components of the lipid barrier for membranes and are a great form of energy storage for the body.

Figure 24.20 Triglyceride Broken Down into a Monoglyceride – Structures of Triglyceride and Monoglyceride – A triglyceride molecule (a) has three fatty acids bound to the glycerol backbone. A monoglyceride (b) has only one fatty acid bound to the glycerol backbone.

Transport of Dietary Lipids by Lipoproteins

In the following section, we will be looking at the story of fats or triglycerides. In the human body, triglycerides are first metabolized by lingual and gastric lipases in the digestive system. In the small intestine, triglycerides are emulsified by bile salts and further broken down into fatty acids and monoglycerides by pancreatic lipases (see Figure 24.21b). However, once they enter the intestinal cells, these triglycerides are repackaged along with cholesterol and proteins within a phospholipid vesicle called chylomicrons (Figure 24.22). This combination of lipids and proteins are called lipoproteins, chylomicron is just one type of lipoprotein. You can think of chylomicrons as a bus carrier for fats and cholesterol so that these hydrophobic molecules can move in the blood circulation that is filled with water. When the chylomicrons leave the intestinal cells by exocytosis, they enter the lacteal ducts, a lymphatic capillary. From the lymphatic system, the chylomicrons are transported to the circulatory system and can either go to the liver or be stored in adipocytes found throughout the body.

Figure 24.21 Digestion and Transport of Dietary Fats Dietary fats are emulsified by bile and further catalyzed by lipases in the small intestine. The products (fatty acids and monoglycerides) are reassembled into triglycerides and package into the formation of chylomicrons.  (OS Bio 2e)

Chylomicrons (OpenStax A&P Textbook: Metabolism)

Dimensions of Lipoproteins (Wiki)

Figure 24.22 Chylomicrons: Chylomicrons contain triglycerides, cholesterol molecules, and other apolipoproteins (protein molecules). They function to carry these water-insoluble molecules from the intestine, through the lymphatic system, and into the bloodstream, which carries the lipids to adipose tissue for storage. (OpenStax A&P Textbook: Metabolism)

Figure 24.23: Lipoprotein Metabolism: A diagram to the endogenous and exogenous pathways of lipoprotein metabolism. Chylomicrons are formed from the exogenous pathway through dietary intake of fats while VLDLs are formed from the endogenous pathway in the liver. The remnants of VLDLs are known as LDLs and they may deposit cholesterol in the blood vessels. HDLs are synthesized by the liver and intestine. HDLs pick up cholesterol in the tissues and return it to the liver. (Wiki)

Besides chylomicrons, there are other types of lipoproteins such as very-low-density lipoproteins (VLDLs), low-density lipoprotein (LDLs), and high-density lipoproteins (HDLs). They differ by the apolipoproteins they contain but also their size (diameter), density, and composition. Since protein is denser than triglyceride, the higher the protein composition, the higher the lipoprotein density. Many lipoproteins are named based on their densities (i.e., high-density lipoproteins contain more proteins than triglycerides). You may wonder where these lipoproteins travel to after they are formed. As they travel in the blood circulation, they will encounter the endothelial cells that line blood vessels, especially in the muscle and adipose tissue. These endothelial cells contain lipoprotein lipase (LPL). Lipoprotein lipase is an enzyme that cleaves triglycerides in the circulating lipoprotein so that the fatty acids can be taken up into tissues. This lipoprotein, now with fewer triglycerides, becomes known as a chylomicron remnant and is directed to the liver. This process of clearing chylomicrons from the blood takes 2-10 hours after a meal which is why people must fast for 12 hours before having their blood lipids (triglycerides, HDL, LDL, etc.) measured. Similarly, the liver produces VLDLs similar to how chylomicrons are produced in the small intestine. The individual components are packaged into VLDL and secreted into circulation. LPL cleaves fatty acids from triglycerides in VLDL, forming the VLDL remnant as it does with chylomicrons. Further action of LPL on the VDLD remnant results in LDL formation. As a result, LDL is composed mostly of cholesterol but contains a specific apolipoprotein (Apo B100) that binds to LDL receptors on the surface of target tissues. Using this receptor, LDLs are endocytosed into target tissues and then broken down into cholesterol and amino acids.

HDLs are made up of mostly protein and are derived from both the liver and intestine. HDL picks up cholesterol from tissues and the blood vessels and returns it to the liver. You are probably familiar with HDL and LDL being referred to as “good cholesterol” and “bad cholesterol,” respectively. This is an oversimplification since LDL and HDL are lipoproteins that transport cholesterol. Your LDL and HDL levels reflect what your body is doing with your cholesterol. What’s so bad about LDL? The LDL enters the endothelium where it is oxidized. This oxidized LDL is engulfed by white blood cells (macrophages) which can lead to the formation of foam cells. The foam cells eventually accumulate so much LDL that they die and form a fatty streak which is the beginning stages of a lesion. In the long run, this can continue to grow until it blocks the blood vessels such as an artery. This can result in a myocardial infarction (heart attack) or a stroke depending on the location of the fatty plaque. The HDL is good in that it scavenges cholesterol from other lipoproteins or cells and returns it to the liver. The figure below shows the formation of the fatty streak and how this can progress to a point where it greatly alters blood flow. (LumenLearning: Lipoproteins)

Figure 24.24 The formation of a lesion in an artery The accumulation of oxidized LDL engulfed by white blood cells (macrophages) can lead to the formation of foam cells. The foam cells can eventually form a fatty plaque and block the blood vessels such as an artery. (Lumen SUNY Nutrition)

Sources and Significance of Blood Cholesterol

Now that we see the damaging effects of fatty plaque formation, you may wonder about where cholesterol comes from and why does it matter? In the body, cholesterol comes from two sources: self-made cholesterol by the liver and dietary cholesterol. Cholesterol is an essential component of cell membranes, where their hydrophobic and hydrophilic regions help regulate the flow of substances into and out of the cell. It is also the precursor of bile acids that help emulsify dietary fats and a building block of many hormones.

Cholesterol is present in most animal-based foods. High consumption of these foods can increase transport by lipoproteins ultimately increasing the blood cholesterol levels and the possibility of forming a fatty plaque. It is known that when the total cholesterol is above 200 mg/dL, there is a higher risk for stroke or coronary artery diseases such as a heart attack. Therefore, it is vital to maintain a healthy blood cholesterol level through a balanced diet, exercising, and sometimes medicine with the guidance of the physician.

The Structure of Cholesterol: (By BorisTM  —  Own work, Public Domain, Wiki)

High Cholesterol Foods

Low Cholesterol Foods – A fruit and vegetable market with people shopping.

Figure 24.25 Cholesterol – Structure, foods with high cholesterol and low or no cholesterol. Other causes of high cholesterol include genetics, being physically inactive, regular smoking, certain medications, and other chronic diseases.

Lipolysis

Besides using glucose as fuel to generate ATP, many cells can use fats. When glucose levels are low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic respiration. To obtain energy from fat, triglycerides must be broken down by hydrolysis into fatty acids and glycerol. This first process is called lipolysis, and it takes place in the cytoplasm of muscle, liver, and adipose tissues. The main goal is to use lipases to break down triglycerides to generate ATP. Triglyceride catabolism yields one glycerol and three fatty acid molecules. Since there are so many more carbons, fats yield more ATPs than carbohydrates. Hence, fats are an important source of energy for the human body.

The fatty acids are further oxidized by fatty acid oxidation or β-oxidation into acetyl CoA in the cytosol, which is used by the Krebs cycle in the mitochondrial matrix. The other product, glycerol, directly enters the glycolysis pathway as dihydroxyacetone phosphate (DHAP). Let us follow the fate of the fatty acid as it gets broken down into smaller units. In the cytosol, a fatty acid is transformed into fatty acyl CoA with the attachment of a coenzyme A molecule. The fatty acyl CoA then combines with carnitine which helps transport the fatty acid across the mitochondrial membrane as acyl-carnitine. Once inside, it is converted back into fatty acyl CoA. Then, the two-carbon units of Acetyl CoA are formed one at a time. Fatty acid oxidation is called β-oxidation because the cleavage occurs at the bond between the α and β carbons (the second and third carbons, respectively). Afterward, the newly formed acetyl CoA enters the Krebs cycle and is used to produce ATP in the same way as acetyl CoA derived from pyruvate. A typical 16-carbon fatty acid can yield as many as 129 ATPs.

Figure 24.26 Structure of a fatty acid with the carbon numbering scheme The cleavage occurs at the bond between the α and β carbons (the second and third carbons, respectively) for β-oxidation (By Jorge Stolfi  —  Own work, CC BY-SA 4.0, Wiki)

Figure 24.27 Breakdown of Fatty Acids During fatty acid oxidation, triglycerides can be broken down into acetyl CoA molecules and used for energy when glucose levels are low.

Ketogenesis and Ketone Body Oxidation

If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies through the process known as ketogenesis in the liver. These ketone bodies can serve as a fuel source if glucose levels are too low in the body. For example, ketone bodies serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose. In both cases, fat stores are liberated to generate energy through the Krebs cycle and will generate ketone bodies when too much acetyl CoA accumulates.

In this ketone synthesis reaction, excess acetyl CoA is converted into hydroxymethylglutaryl CoA (HMG CoA). HMG CoA is an intermediate that is subsequently converted into ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone, see Figure 24.28). Interestingly, HMG CoA is also the precursor for a pathway to form cholesterol.

Figure 24.28 Ketogenesis Excess acetyl CoA is diverted from the Krebs cycle to the ketogenesis pathway. This reaction occurs in the mitochondria of liver cells. The result is the production of ketone bodies found in the blood. (By Sav vas – Own workSources:File:Ketogenesis.pngFile:Acetyl-CoA.svgFile:Acetoacetyl-CoA.svgFile:Aceton.svgFile:Acetoacetate to beta-hydroxybutyrate.svgFile:HMG coenzyme A.svg, CC0, Wiki)

Ketone Body Oxidation

You may have heard about keto diets, which are diets that increase the blood concentration of ketone bodies. In this section, we will look at the physiological role of ketone bodies in the body. All our cells can use glucose as fuel, but some prefer using fats. The brain was once thought to be limited to using glucose for generating ATP. It is now known the brain can use ketone bodies as an alternative energy source. This keeps the brain functioning when glucose is limited. When ketone bodies are produced faster than they can be used, they can be further broken down into CO2 and acetone which are removed by exhalation. One symptom of ketogenesis is that the patient’s breath smells sweet like acetone. This indicates a diabetic may not be properly controlling their disease. The carbon dioxide produced can also acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in diabetics.

After ketone bodies are made in the liver, they leave the hepatocytes and diffuse into circulation. Besides the brain, heart muscle and adrenal cortex can also use ketone bodies. In these organs, ketone bodies are oxidized to produce energy. When β-hydroxybutyrate is oxidized, NADH is released and a coenzyme A (CoA) molecule is added to acetoacetate forming acetoacetyl CoA. A bond breaks within the acetoacetyl CoA, splitting the molecule in two. Another free CoA is attached resulting in two acetyl CoA molecules. These two acetyl CoA molecules are then processed through the Krebs cycle to generate energy (Figure 24.27). It is interesting to note that the liver lacks the enzyme to utilize ketone bodies, so it cannot use it for ATP production.

Figure 24.29 Ketone Oxidation When glucose is limited, ketone bodies can be oxidized to produce acetyl CoA to be used in the Krebs cycle to generate energy.

Lipogenesis

Earlier we discussed what happens in the body when glucose concentrations are limited. When glucose levels are plentiful, we can store them in the form of fats. Extra glucose leads to more production of acetyl CoA by glycolysis which can be converted into triglycerides (fats) with the stimulation of insulin. Excess dietary protein and fats can also be converted into triglycerides. This process is called lipogenesis and it takes place in the cytoplasm of adipocytes and hepatocytes. When you eat more carbohydrates, proteins, and fats than your body needs the excess acetyl CoA turns into triglycerides.

Lipogenesis begins with acetyl CoA and advances by the subsequent addition of a two-carbon unit from another acetyl CoA; this process is repeated until fatty acids are the appropriate length. You can think of it as the opposite of fatty acid oxidation. Because this is a bond-creating anabolic process, ATP is consumed. The triglycerides and lipids are the high-energy molecules that are stored in adipose tissue until they are needed.

Although lipogenesis occurs in the cytoplasm, the necessary acetyl CoA is created in the mitochondria and cannot be transported across the mitochondrial membrane. To solve this problem, our cells use citrate as a shuttle system. First, pyruvate is converted into oxaloacetate and acetyl CoA by two different reactions. Second, oxaloacetate and acetyl CoA combine to form citrate, which can cross the mitochondrial membrane and enter the cytoplasm. In the cytoplasm, citrate is converted back into oxaloacetate and acetyl CoA. Oxaloacetate is converted into malate and then into pyruvate. Pyruvate crosses back across the mitochondrial membrane to wait for the next cycle of lipogenesis. The acetyl CoA is converted into malonyl CoA that is used to synthesize fatty acids. The figure below summarizes the pathway of lipogenesis.

Figure 24.30 Lipogenesis Pyruvate and Citrate are used as a shuttle system to help move the acetyl CoA into the cytosol for lipogenesis. (OpenStax Lipid Metabolism)

24.4 Protein Metabolism

So far, we have looked at how carbohydrates and lipids are being metabolized in the body. Have you ever wondered about how proteins are being metabolized? Proteins can be structural molecules and enzymes that catalyze all biochemical reactions, hormones, receptors, and transporters. In addition to these functions, proteins also hold the potential to serve as a metabolic fuel source.

Unlike carbohydrates and lipids, proteins are not stored for later use. Excess proteins must be converted into glucose or triglycerides and then be used to supply energy or stored in glycogen or fat tissue. The body synthesizes proteins from amino acids and we have 22 proteinogenic amino acids that are incorporated biosynthetically into proteins during translation. Among them, 9 are regarded as essential amino acids because humans cannot synthesize them or they are synthesized in such low amounts that they must be consumed as part of the diet. These essential amino acids are valine, isoleucine, leucine, methionine, phenylalanine, tryptophan, threonine, histidine, and lysine. Others are nonessential amino acids that we can make from other molecules. Beef, fish, poultry, eggs, and milk are known as complete proteins because they contain all essential amino acids. Vegetables, grains, and legumes (beans and peas) are called incomplete proteins since they do not contain all essential amino acids.

The digestion of proteins begins in the stomach. When protein-rich foods enter the stomach, they are greeted by a mixture of the enzyme pepsin and hydrochloric acid (HCl). The latter produces an environmental pH of 1.5–3.5 that denatures proteins. Denatured proteins are linear; they are no longer in their globular shape. Pepsin and the pancreatic digestive enzymes (trypsin, chymotrypsin, and elastase) can now break the peptide bonds. Trypsin and chymotrypsin break down large proteins into smaller peptides, a process called proteolysis (Figure 24.31). These smaller peptides are catabolized further into their constituent amino acids, which can be transported across the intestinal mucosa. The amino acids are transferred into the bloodstream and delivered to the liver and cells throughout the body.

Figure 24.31 Digestive Enzymes and Hormones: Enzymes in the stomach and small intestine break down proteins into amino acids. HCl in the stomach aids in proteolysis, and hormones secreted by intestinal cells direct the digestive processes.

Freely available amino acids are taken up by cells and are used to create new proteins. If amino acids exist in excess, the body has no capacity or mechanism for their storage; thus, they are converted into glucose, triglycerides, ketones, or decomposed. During the metabolism of amino acids, the amino groups (NH3) are removed. As a result, amino acid catabolism produces not only hydrocarbons for other pathways but nitrogenous waste products known as ammonia. Because high concentrations of ammonia are toxic, our cells use the urea cycle to process the nitrogenous waste and facilitate its excretion from the body.

Figure 24.32 Amino Acid Structure An amino acid includes an α carbon, a hydrogen, a carboxyl group, an amino group, and the side chain (R).

Urea cycle

Ammonia (NH3) ionizes readily to form ammonium (NH4+). The accumulation of these nitrogenous wastes is toxic to the body. The urea cycle is a set of biochemical reactions that produces urea from ammonium ions and it occurs primarily in the liver but also in the kidney to a lesser extent. In these reactions, an amine group, or ammonium ion, from the amino acid is exchanged with a keto group on another molecule. This transamination event creates a molecule that is necessary for the Krebs cycle and an ammonium ion that enters the urea cycle to be eliminated (Figure 24.31). In summary, ammonium is combined with CO2, resulting in urea and water in the urea cycle. Urea is eliminated through the kidneys in the urine.

Figure 24.33 Urea Cycle: Nitrogen is transaminated, creating ammonia and intermediates of the Krebs cycle. Ammonia is processed in the urea cycle to produce urea that is eliminated through the kidneys. (OpenStax)

Amino acids can also be used as a source of energy, especially in times of starvation. Because the degradation of amino acids results in the creation of metabolic intermediates (such as pyruvate, acetyl CoA, acetoacetyl CoA, oxaloacetate, and α-ketoglutarate) amino acids can serve as a source of energy production through the Krebs cycle (Figure 24.31). Figure 24.32 summarizes the pathways of catabolism and anabolism for carbohydrates, lipids, and proteins.

Figure 24.34 Energy from Amino Acids: Amino acids can be broken down into precursors for glycolysis or the Krebs cycle. Amino acids (in bold) can enter the cycle through more than one pathway. (OpenStax A&P Textbook: Protein Metabolism)

Figure 24.35 Catabolic and Anabolic Pathways: Nutrients follow a complex pathway from ingestion through anabolism and catabolism to energy production.

24.5 The Metabolic States of the Body

We eat periodically throughout the day; however, the organs, especially the brain, need a continuous supply of glucose. How does the body meet this constant energy demand? The body processes the food so that we can use it immediately or store it for later energy demand even during times of fasting and starvation.

Absorptive state

Imagine that you just had a plate of loco moco. Let us consider what the body will do with all the nutrients. The absorptive state, or the fed state, occurs after a meal when the body is digesting the food and absorbing the nutrients. Digestion begins the moment you put food into your mouth, as the food is broken down into its constituent parts to be absorbed through the intestinal wall. The sugars and amino acids are transported into the bloodstream and fats are transported to the lymphatic system. From here they are transported to the liver, adipose tissue, or muscle cells that will process and then use or store the molecules.

Depending on the amounts and types of nutrients ingested, the absorptive state can linger for up to four hours. The ingestion of food increases blood glucose concentrations which stimulate pancreatic beta cells to release insulin. Insulin initiates the absorption of blood glucose by liver hepatocytes, adipose, and muscle cells. Once inside these cells, glucose is immediately converted into glucose-6-phosphate which creates a concentration gradient ensuring continued glucose absorption.

If energy demand occurs shortly after eating, the dietary fats, proteins, and sugars recently ingested will be processed and used immediately for ATP generation. If energy demand doesn’t occur, the excess glucose is stored as glycogen in the liver and muscle cells, or as fat in adipose tissue; excess dietary fat is also stored as triglycerides in adipose tissues. In addition to promoting glucose uptake, insulin stimulates glycogenesis in the liver and muscle cells and promotes the synthesis of protein in muscle.

Figure 24.36 summarizes the metabolic processes occurring in the body during the absorptive state.

Figure 24.36 Absorptive State: During the absorptive state, the body digests food and absorbs the nutrients. (OpenStax A&P Textbook: Metabolic State)

Post-absorptive state

The postabsorptive state, or the fasting state, occurs once food has been digested, absorbed, and stored. You commonly fast overnight but skipping meals during the day puts your body in a postabsorptive state as well. During this state, the body must initially rely on stored glycogen. As glucose levels in the blood begin to drop, insulin levels also drop. Glycogen and triglyceride storage slows. However, due to the demands of the tissues and organs, blood glucose levels must be maintained within the normal range of 80–120 mg/dL. To achieve this concentration, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon acts upon the liver cells, where it inhibits the synthesis of glycogen and stimulates the breakdown of stored glycogen into glucose monomers through glycogenolysis. The freed glucose is released from the liver to raise blood glucose levels. During fasting, gluconeogenesis will also begin in the liver to replace the glucose that has been used by the peripheral tissues.

Also, during the postabsorptive state, lipolysis and protein catabolism will occur. In adipose tissues, triglycerides are broken down into fatty acids and glycerol where they can be used as fuels to generate ATP molecules. In skeletal muscles, some proteins may be catabolized into amino acids. These amino acids can travel to the liver and be converted into glucose as fuels. Figure 24.37 summarizes the metabolic processes occurring in the body during the postabsorptive state.

Figure 24.37 Postabsorptive State: During the postabsorptive state, the body must rely on stored glycogen for energy. (OpenStax)

Metabolism during Fasting and Starvation

Fasting refers to going without food for many hours or a few days, whereas starvation means not having adequate food intake for weeks or months. These are very stressful situations, and they affect the body in many ways. When the body is deprived of nourishment for an extended period, it goes into “survival mode.” The priority for survival is to provide enough glucose or fuel for the brain. These sources will come from glycogens that are mainly stored in the liver and the skeletal muscles. However, glycogen can be depleted within a few hours after the onset of fasting. Next, stored triglycerides will be used as fuels. Through lipolysis, fatty acids and glycerol will be released so that cells can use them for energy generation. Because glucose levels are very low during starvation, glycolysis will shut off in cells that can use alternative fuels. For example, muscles will switch from using glucose to fatty acids. As previously explained, fatty acids can be converted into acetyl CoA and processed through the Krebs cycle to make ATP. Pyruvate, lactate, and alanine from muscle cells cannot be converted into acetyl CoA, and therefore don’t enter the Krebs cycle. These are instead exported to the liver for the synthesis of glucose through gluconeogenesis. As starvation continues, and more glucose is needed, glycerol from fatty acids can be liberated and used as a source for gluconeogenesis.

After several days of starvation, ketone bodies become the major source of fuel for the heart and other organs. Fatty acids and triglyceride stores are used to create ketones which prevent the continued breakdown of proteins. Once fat stores are depleted, proteins in muscle are broken down for gluconeogenesis. Overall, enduring starvation is largely dependent on the amount of fat and protein stored in the body.

24.6 Energy and Heat Balance

Being in Hawaiʻi, we often think of a hot sunny day where we swim and sweat it off at the beach. However, you will be pleasantly surprised to feel the freezing temperature when you visit Mauna Kea on the Big Island or Haleakalā on Maui. No matter where we go, the body temperature is carefully regulated through a process called thermoregulation. Through this process, we can maintain a normal temperature within certain boundaries, even when the surrounding temperature is very different. The core temperature of the body remains steady at around 36.5–37.5 °C (or 97.7–99.5 °F). In the process of ATP production by cells throughout the body, about 60 percent of the energy produced is in the form of heat which is used to maintain body temperature.

The hypothalamus in the brain is the master thermostat to regulate the body’s core temperature (Figure 24.38). If the temperature is too high, the hypothalamus can initiate several processes to lower it. These include increasing blood circulation to the surface of the body to allow for heat dissipation which also initiates sweating and surface evaporation to cool the skin surface. Conversely, if the temperature falls below the set core temperature, the hypothalamus can initiate shivering to generate heat. Additionally, when body temperature drops very low, blood vessels to the skin constrict, redistributing most of the blood away from the skin and towards the core where it will hold more heat. Thermoregulation is an example of negative feedback. Moreover, thyroid hormone will stimulate more energy use and heat production by cells throughout the body. An environment is said to be thermoneutral when the body does not expend or release energy to maintain its core temperature. Most of the time, the body loses heat through heat exchange mechanisms.

Figure 24.38 Hypothalamus Controls Thermoregulation: The hypothalamus controls thermoregulation. (OpenStax A&P Textbook: Thermoregulation)

Mechanisms of Heat Exchange

When the environment is not thermoneutral, the body uses four mechanisms of heat exchange to maintain homeostasis: conduction, convection, radiation, and evaporation. Each of these mechanisms relies on the property of heat to flow from a higher concentration to a lower concentration; therefore, each of the heat exchange mechanisms varies in rate according to the temperature and conditions of the environment.

Conduction is the transfer of heat by two objects that are in direct contact with one another. It occurs when the skin comes in contact with a cold or warm object. For example, when holding a glass of ice water, heat from your skin will warm the glass, and in turn melt the ice. Alternatively, on a cold day, you might warm up by wrapping your cold hands around a hot mug of Hawaiian coffee. Only about three percent of the body’s heat is lost through conduction.

Convection is the transfer of heat to the air surrounding the skin through direct contact. The warmed air rises away from the body and is replaced by cooler air that is subsequently heated. A fan speeds up this process. Convection can also occur in water. When the water temperature is lower than the body’s temperature, the body loses heat by warming the water closest to the skin, which moves away to be replaced by cooler water. Wearing a wetsuit helps keep your body warm by preventing this warmed water from moving away from your skin surface. About 15 percent of the body’s heat is lost through convection.

Radiation is the transfer of heat via infrared waves. This occurs between any two objects when the temperatures differ without physical contact. A radiator can warm a room via radiant heat. On a sunny day, the radiation from the sun warms the skin. The same principle works from the body to the environment. About 60 percent of the heat lost by the body is lost through radiation.

Evaporation is the transfer of heat by the evaporation of water. Because it takes a great deal of energy for a water molecule to change from a liquid to a gas, evaporating water (in the form of sweat) takes with it a great deal of energy from the skin. However, the rate at which evaporation occurs depends on relative humidity—lower humidity increases evaporation. Sweating is the primary means of cooling the body during exercise, whereas, at rest, about 20 percent of the heat lost by the body occurs through evaporation.

Metabolic Rate and BMR

The metabolic rate is the amount of energy consumed minus the amount of energy the body expends. The basal metabolic rate (BMR) describes the amount of daily energy expended by humans at rest, in a neutrally temperate environment, while in the postabsorptive state. It measures how much energy the body needs for normal, basic, daily activity. About 70 percent of all daily energy expenditure comes from the basic functions of the organs in the body. Another 20 percent comes from physical activity, and the remaining 10 percent is necessary for body thermoregulation or temperature control. Of course, these percentages can change drastically depending on the overall physical activity of an individual. This rate will be higher if a person is more active or has more lean body mass. As you age, the BMR generally decreases as the percentage of less lean muscle mass decreases.

24.7 Nutrition and Diet

The carbohydrates, lipids, and proteins in the foods you eat are used for energy to power molecular, cellular, and organ system activities. Since the capacity for glycogen storage is limited, excess energy is primarily stored as fats. Diet, both what and how much you eat, has a dramatic impact on your health. Eating too much or too little food can lead to serious medical issues, such as cardiovascular disease, cancer, anorexia, and diabetes.

Food and Metabolism

Calories

The amount of energy that is needed or ingested per day is measured in calories. The nutritional Calorie (C), also known as the kilocalorie, is the amount of heat it takes to raise 1 kg (1000 g) of water by 1 °C. This is different from the calorie (c) used in the physical sciences, which is the amount of heat it takes to raise 1 g of water by 1 °C. When we refer to “calorie,” we are referring to the nutritional Calorie.

On average, a person needs 1500 to 2000 calories per day to sustain (or carry out) daily activities. The total number of calories needed by one person is dependent on their body mass, age, height, gender, activity level, and the amount of exercise per day. If exercise is a regular part of one’s day, more calories are required. As a rule, people underestimate the number of calories ingested, and overestimate the amount they burn through exercise. This misconception can lead to the ingestion of too many calories. The accumulation of an extra 3500 calories adds one pound of weight. If an excess of 200 calories per day is ingested, one extra pound of body weight will be gained every 18 days. At that rate, an extra 20 pounds can be gained over a year. Of course, this increase in calories could be offset by increased exercise. Running or jogging one mile burns almost 100 calories. In general, the number of calories ingested and the number of calories burned determine the overall weight. To lose weight, the number of calories burned per day must exceed the number ingested. The type of food ingested also affects the body’s metabolic rate. The processing of carbohydrates requires less energy than the processing of proteins. In fact, the breakdown of carbohydrates requires the least amount of energy, whereas the processing of proteins demands the most energy.

Diet

To help provide guidelines regarding the types and quantities of food that should be eaten every day, the USDA has updated its food guidelines from MyPyramid to MyPlate. They have put the recommended elements of a healthy meal into the context of a place setting of food. MyPlate categorizes food into the standard six food groups: fruits, vegetables, grains, protein foods, dairy, and oils. The accompanying website gives clear recommendations regarding the quantity and type of each food that you should consume each day, as well as identifying which foods belong in each category. The accompanying graphic (Figure 24.37) gives a clear visual with general recommendations for a healthy and balanced meal. The guidelines recommend making about half your plate fruits and vegetables. The other half is grains and protein, with a slightly higher quantity of grains than protein. Dairy products are represented by a drink, but the quantity can be applied to other dairy products as well.

Figure 24.39 MyPlate: The U.S. Department of Agriculture developed food guidelines called MyPlate to help demonstrate how to maintain a healthy lifestyle. (OpenStax A&P Textbook: Nutrition and Diet)

ChooseMyPlate.gov provides extensive online resources for planning a healthy diet and lifestyle, including offering weight management tips and recommendations for physical activity. It also includes the SuperTracker, a web-based application to help you analyze your own diet and physical activity.

Table 24.3: 200 Calories: Comparing 200 calories of various foods

Vitamins

Vitamins are organic compounds required for some biochemical reactions in the body. There are several processes involved, including mineral and bone metabolism, and cell and tissue growth as cofactors for energy metabolism (see Table 24.4 and Table 24.5). Most vitamins are obtained through the diet, but some can be made. For example, the body synthesizes vitamin A from the β-carotene in orange vegetables like carrots and sweet potatoes. Vitamins are classified as either fat-soluble or water-soluble.

Fat-Soluble Vitamins

Fat-soluble vitamins A, D, E, and K, are absorbed through the intestinal tract with lipids in chylomicrons. Vitamin D is also synthesized in the skin through exposure to sunlight. Because they are carried in fat-soluble chylomicrons, vitamins can accumulate in the lipids stored in the body. If excess vitamins are retained in the lipid stores in the body, hypervitaminosis can result.

Vitamin A is a group of organic molecules obtained not only from yellow and orange fruits and vegetables but also from eggs, milk, and liver. It is important in the eye and immune functions. Vitamin E comes from seeds and nuts, avocados, and some vegetable oils. It is a powerful antioxidant. A deficiency of vitamin E may cause anemia. Vitamin K is important in the production of several clotting factors in the liver. This fat-soluble vitamin is found in dark green leafy vegetables. Bacteria in the gut help convert vitamin K to one of its active forms.

Figure 24.41: Types of Fat-Soluble Vitamins. (LibreTexts)

Water-Soluble Vitamins

Water-soluble vitamins, including the eight B vitamins and vitamin C, are absorbed with water into the gastrointestinal tract. These vitamins move easily through the water-based bodily fluids. Due to their high solubility, excess water-soluble vitamins are excreted in the urine. Therefore, hypervitaminosis of water-soluble vitamins rarely occurs, except with an extreme excess of vitamin supplements.

B vitamins are a varied group of molecules that play diverse roles in metabolism. They play a role in CoA, FAD, and NAD synthesis, carbohydrate and protein metabolism, and protein and DNA production. They are obtained from foods such as meats, dark green leafy vegetables, fish, dairy, and some grains. Vitamin C is a water-soluble vitamin obtained from fruits, especially citrus, and other fresh foods. Vitamin C is required for collagen production, a necessary component of connective tissue, bones, and teeth.

Table 24.4 Fat-soluble Vitamins 

A retinal or β-carotene	D cholecalciferol	E tocopherols	K phylloquinone

Table 24.5 Vitamin Structure – Fat-soluble Vitamins

B1 thiamine	B2 riboflavin	B3 niacin	B5 pantothenic acid
B6 pyridoxine	B7 biotin	B9 folic acid	B12 cyanocobalamin
C ascorbic acid

Table 24.6 Vitamin Structure – Water-soluble Vitamins 

Table 24.7 Water-soluble Vitamins

Minerals

By weight, most of the human body consists of just four elements: carbon, hydrogen, nitrogen, and oxygen. Minerals make up the remaining four percent. Some of these minerals are in relatively large abundance such as: potassium, sodium, calcium, phosphorus, magnesium, and chloride. These are known as the major minerals. There are also trace minerals that are very important to the body’s functions. Table 24.8 and Table 24.9 summarizes minerals and their function in the body.

Major Minerals

The most common macrominerals in the body are calcium and phosphorus, both of which are stored in the skeleton and necessary for the hardening of bones. Calcium plays a role in blood clotting, neurotransmitter release, and muscle contraction. Phosphorus plays several diverse roles, including forming the phosphate groups, which are critical components of DNA/RNA and ATP. Most minerals are ionized as either anions or cations, also known as electrolytes. Sodium electrolytes are critical for BP and neuron and myofiber physiology.

Trace Minerals

Trace minerals include iron, a key part of hemoglobin, the molecule responsible for carrying oxygen around the body. Iodine, selenium, and zinc are crucial for a healthy thyroid. Sulfur is a part of some amino acids. This element is responsible for forming disulfide bridges that play a role in forming the shape of some proteins as well as forming part of the iron-sulfur clusters in the electron transport chain (ETC) of mitochondria. Even though trace minerals are only needed in small amounts, their presence is essential to a healthy body.

Table 24.8 Major Minerals 

Table 24.9 Trace Minerals 

Now that we understand how the body works and what it needs to work properly. It is essential to be mindful of the body and supply it with the needed nutrients. The idea is to have a balanced diet and an active lifestyle.

Chapter Summary

Quiz

Links and Attributions:

1. Cyanide poisoning (Wikipedia: Cyanide)
2. Treatment of cyanide poisoning (CDC).
3. LumenLearning: Lipoproteins (CC BY)
4. ResearchGate: Types of Lipoproteins (copyrighted).
5. Hypothermia (Mayo Clinic)
6. Fat-Soluble Vitamins. (LibreTexts)
7. About Hawaiian Foods and Ancient Food Customs (UH Mānoa press) Fujita R, Braun KL, Hughes CK. The traditional Hawaiian diet: a review of the literature. Pac Health Dialog. 2004 Sep;11(2):250-9. PMID: 16281710.

Key Terms

absorptive state

also called the fed state; the metabolic state occurring during the first few hours after ingesting food in which the body is digesting food and absorbing the nutrients

acetyl coenzyme A (acetyl CoA)

starting molecule of the Krebs cycle

anabolic hormones

hormones that stimulate the synthesis of new, larger molecules

anabolic reactions

reactions that build smaller molecules into larger molecules

ATP synthase

protein pore complex that creates ATP

basal metabolic rate (BMR)

amount of energy expended by the body at rest

bile salts

salts that are released from the liver in response to lipid ingestion and surround the insoluble triglycerides to aid in their conversion to monoglycerides and free fatty acids

body mass index (BMI)

relative amount of body weight compared to the overall height; a BMI ranging from 18–24.9 is considered normal weight, 25–29.9 is considered overweight, and greater than 30 is considered obese

calorie

amount of heat it takes to raise 1 kg (1000 g) of water by 1 °C

catabolic hormones

hormones that stimulate the breakdown of larger molecules

catabolic reactions

reactions that break down larger molecules into their constituent parts

cellular respiration

production of ATP from glucose oxidation via glycolysis, the Krebs cycle, and oxidative phosphorylation

chylomicrons

vesicles containing cholesterol and triglycerides that transport lipids out of the intestinal cells and into the lymphatic and circulatory systems

chymotrypsin

pancreatic enzyme that digests protein

citric acid cycle

also called the Krebs cycle or the tricarboxylic acid cycle; converts pyruvate into CO2 and high-energy FADH2, NADH, and ATP molecules

conduction

transfer of heat through physical contact

convection

transfer of heat between the skin and air or water

elastase

pancreatic enzyme that digests protein

electron transport chain (ETC)

ATP production pathway in which electrons are passed through a series of oxidation-reduction reactions that forms water and produces a proton gradient

energy-consuming phase

first phase of glycolysis, in which two molecules of ATP are necessary to start the reaction

energy-yielding phase

second phase of glycolysis, during which energy is produced

evaporation

transfer of heat that occurs when water changes from a liquid to a gas

FADH2

high-energy molecule needed for glycolysis

fatty acid oxidation

breakdown of fatty acids into smaller chain fatty acids and acetyl CoA

flavin adenine dinucleotide (FAD)

coenzyme used to produce FADH2

glucokinase

cellular enzyme, found in the liver, which converts glucose into glucose-6-phosphate upon uptake into the cell

gluconeogenesis

process of glucose synthesis from pyruvate or other molecules

glucose-6-phosphate

phosphorylated glucose produced in the first step of glycolysis

glycogen

form that glucose assumes when it is stored

glycolysis

series of metabolic reactions that breaks down glucose into pyruvate and produces ATP

hexokinase

cellular enzyme, found in most tissues, that converts glucose into glucose-6-phosphate upon uptake into the cell

hydroxymethylglutaryl CoA (HMG CoA)

molecule created in the first step of the creation of ketone bodies from acetyl CoA

insulin

hormone secreted by the pancreas that stimulates the uptake of glucose into the cells

ketone bodies

alternative source of energy when glucose is limited, created when too much acetyl CoA is created during fatty acid oxidation

Krebs cycle

also called the citric acid cycle or the tricarboxylic acid cycle, converts pyruvate into CO2 and high-energy FADH2, NADH, and ATP molecules

lipogenesis

synthesis of lipids that occurs in the liver or adipose tissues

lipolysis

breakdown of triglycerides into glycerol and fatty acids

metabolic rate

amount of energy consumed minus the amount of energy expended by the body

metabolism

sum of all catabolic and anabolic reactions that take place in the body

minerals

inorganic compounds required by the body to ensure proper function of the body

monosaccharide

smallest, monomeric sugar molecule

NADH

high-energy molecule needed for glycolysis

nicotinamide adenine dinucleotide (NAD)

coenzyme used to produce NADH

oxidation

loss of an electron

oxidation-reduction reaction

(also, redox reaction) pair of reactions in which an electron is passed from one molecule to another, oxidizing one and reducing the other

oxidative phosphorylation

process that converts high-energy NADH and FADH2 into ATP

pancreatic lipases

enzymes released from the pancreas that digest lipids in the diet

pepsin

enzyme that begins to break down proteins in the stomach

polysaccharides

complex carbohydrates made up of many monosaccharides

postabsorptive state

also called the fasting state; the metabolic state occurring after digestion when food is no longer the body’s source of energy and it must rely on stored glycogen

proteolysis

process of breaking proteins into smaller peptides

pyruvate

three-carbon end product of glycolysis and starting material that is converted into acetyl CoA that enters the Krebs cycle

radiation

transfer of heat via infrared waves

reduction

gaining of an electron

salivary amylase

digestive enzyme that is found in the saliva and begins the digestion of carbohydrates in the mouth

terminal electron acceptor

oxygen, the recipient of the free hydrogen at the end of the electron transport chain

thermoneutral

external temperature at which the body does not expend any energy for thermoregulation, about 84 °F

thermoregulation

process of regulating the temperature of the body

transamination

transfer of an amine group from one molecule to another as a way to turn nitrogen waste into ammonia so that it can enter the urea cycle

tricarboxylic acid cycle (TCA)

also called the Krebs cycle or the citric acid cycle; converts pyruvate into CO2 and high-energy FADH2, NADH, and ATP molecules

triglycerides

lipids, or fats, consisting of three fatty acid chains attached to a glycerol backbone

trypsin

pancreatic enzyme that activates chymotrypsin and digests protein

urea cycle

process that converts potentially toxic nitrogen waste into urea that can be eliminated through the kidneys

vitamins

organic compounds required by the body to perform biochemical reactions like metabolism and bone, cell, and tissue growth