LEHNINGER PRINCIPLES OF BIOCHEMISTRY - VOL 2. BIOENERGETICS AND METABOLISM - 2014

PART II. BIOENERGETICS AND METABOLISM

Class="center">We believe that any tissue, and more importantly, any Cell in the Organism secretes... into the Blood specific substances, or Enzymes, that affect all other Cells, integrating them via a mechanism other than The Nervous system.

Charles-Édouard Brown-Séquard and Jacques-Arsène d'Arsonval, article in Comptes Rendus de la Société de Biologie, 1891

23. HORMONAL REGULATION AND METABOLIC INTEGRATION IN MAMMALS

In Chapters 13 through 22, we discussed METABOLISM at the level of the individual cell, focusing primarily on pathways common to nearly all cells, both prokaryotic and eukaryotic. We have seen how metabolic processes are regulated within The Cell at the level of individual enzymatic reactions through changes in substrate availability, allosteric mechanisms, and phosphorylation or other covalent modifications of enzymes.

To fully understand The Role of individual metabolic pathways and their modes of regulation, we must examine the problem at the whole-organism level. The most essential features of Multicellular Organisms are cellular differentiation and the division of labor. The specialization of Tissues and Organs in a complex organism such as a human implies the existence of specific metabolic pathways and unique Energy Requirements. The METABOLIC ACTIVITY OF various tissues is coordinated and integrated by hormonal signals, which optimize the distribution of energy-rich compounds and precursors to each organ.

In this chapter, we explore mammalian metabolism, paying special attention to the specialized metabolism of several major organs and tissues, as well as the integration of each specialized metabolic pathway into the metabolism of the entire organism. We begin by outlining the broad range of HORMONES and hormonal mechanisms, and then turn to the tissue-specific Functions regulated by these mechanisms. We discuss the distribution of BIOLOGICALLY ACTIVE SUBSTANCES across various organs, emphasizing The Central Role of the Liver, and explore metabolic cooperation among organs. To illustrate the unifying role of hormones, we describe the interplay of Insulin, Glucagon, and epinephrine in coordinating Energy Metabolism in Muscle, liver, and adipose tissue. Finally, using Metabolic Disorders in Diabetes Mellitus as an example, we demonstrate the crucial importance of hormonal regulation in metabolism.

We will also discuss the mechanisms of Hormonal Regulation of body weight and The impact of excess body weight on The Development of metabolic syndrome and diabetes.

23.1. Hormones: Diverse Structures for Diverse Functions

Essentially, in a complex organism, nearly all processes are regulated by one or more hormones: the maintenance of blood pressure, changes in blood volume and electrolyte balance, Embryogenesis, sexual differentiation, development and reproduction, hunger, feeding behavior, Digestion, and the distribution of energy-rich substances, among others. We examine Methods for identifying and measuring hormone concentrations, their interactions with receptors, and discuss the various types of hormones.

Metabolism in mammals is coordinated through the neuroendocrine system. Individual cells in one tissue sense changes in systemic conditions and respond by secreting chemical messengers that travel to other cells within the same or a different tissue, where they bind to a receptor molecule and trigger Changes in the target cell. In neural transmission (Fig. 23-1a), a chemical messenger (a neurotransmitter, such as acetylcholine) travels a distance of only about a micrometer, crossing the synaptic cleft to the next neuron. In hormonal signaling, the messengers are hormones carried by the bloodstream to neighboring cells or to distant organs and tissues. To reach their target cells, hormones may travel a distance of 1 m or more (Fig. 23-1b). Except for this difference, the two chemical signaling mechanisms—neuronal and hormonal—are remarkably similar. Epinephrine and norepinephrine, for example, function as Neurotransmitters in Brain synapses and smooth muscle, and as hormones regulating energy metabolism in The Liver and Muscles. Building on our Structure/133.html">Discussion of energy metabolism in previous chapters, we now describe cellular signaling, with a particular focus on the Action of Hormones. Note that most of the fundamental signaling mechanisms discussed here are also characteristic of neurotransmitter action.

Fig. 23-1. Signaling via the neuroendocrine system. (a) In neural transmission, electrical signals originate in the neuron cell body and travel very rapidly to the axon terminal, where neurotransmitters are released and subsequently diffuse to target cells. Such target cells (another neuron, a myocyte, or a secretory cell) must be located no more than a few micrometers away from the site of neurotransmitter release. (b) In the Endocrine System, hormones are secreted into the bloodstream, which can transport them throughout the body to target tissues that may be a meter or more away from the secreting cell. Both neurotransmitters and hormones interact with specific receptors On the surface or inside their target cells, eliciting a biological response.

Biological Studies Are Essential for the Discovery and Purification of Hormones

How were hormones discovered and isolated? First, it was established that physiological processes in one tissue depend on signals originating from another tissue. For example, the Pancreas produces a substance that affects the volume and composition of urine; this was the first hormone ever discovered—insulin (see Box 23-1). Once the Physiological Effect of a putative hormone is established, quantitative studies are conducted to determine its biological role. In the case of insulin, the research involved injecting crude pancreatic extracts (a source of insulin) into insulin-deficient experimental animals and then analyzing the resulting changes in blood and urine glucose concentrations. To isolate the hormone, extracts containing the putative hormone are fractionated using the same biochemical techniques employed for isolating other Biomolecules (Thin-Layer Chromatography and other chromatographic methods, Electrophoresis), and each fraction is then tested for hormonal activity. Once the substance is purified, its Composition and Structure can be determined.

This approach to hormone research may seem deceptively simple. Hormones are extremely potent substances and are therefore produced in minuscule amounts. Obtaining a sufficient quantity of a hormone to characterize it chemically often involves biochemical work on a massive scale. For instance, when Roger Guillemin and Andrew Schally independently isolated and characterized thyrotropin-releasing hormone (TRH) from the Hypothalamus, Schally's group processed 20 tons of hypothalamus tissue from approximately 2 million sheep, whereas Guillemin's group prepared extracts from the tissues of about 1 million pigs! TRH turned out to be a tripeptide derivative, Glu-His-Pro (Fig. 23-2). Once The structure of the hormone was determined, it became possible to synthesize it chemically in large quantities for use in PHYSIOLOGICAL AND BIOCHEMICAL research.

Fig. 23-2. Structure of thyrotropin-releasing hormone (TRH). Isolated through heroic efforts from hypothalamic extracts, TRH was found to be a tripeptide derivative of Glu-His-Pro. The carboxyl group of the side chain of the N-terminal Glu forms an amide (highlighted in red) with the α-amino group of the residue, converting it to pyroglutamate, while the carboxyl group of the C-terminal Pro is converted to an amide (red -NH₂). Such modifications are typical of low-molecular-weight Peptide Hormones. In a protein with an Mr of ~50,000, the charges on the N- and C-terminal groups contribute relatively little to the overall charge of the protein molecule, but in a tripeptide, the presence of these two charged groups largely determines The properties of the peptide. Amide formation neutralizes these charges.

The 1977 Nobel Prize in Physiology or Medicine for work on Hypothalamic hormones was shared between Schally and Guillemin ("for their discoveries concerning the peptide hormone production of the brain"), on the one hand, and Rosalyn Yalow ("for the development of radioimmunoassays of peptide hormones"), on the other. Yalow (along with Solomon A. Berson) pioneered The Use of the highly sensitive radioimmunoassay (RIA) method to measure peptide hormones and developed techniques for studying hormone action. RIA revolutionized hormone research by making the rapid, quantitative, and specific measurement of hormones at ultra-low concentrations possible.

Box 23-1. MEDICINE. The Discovery of Hormones: The Arduous Path to Pure Insulin

Millions of people with type 1 (insulin-dependent) diabetes mellitus inject pure insulin daily to compensate for the lack of this vital hormone produced by their own pancreatic β-cells. Insulin injections cannot cure diabetes, but they allow an individual who might otherwise die young to live a long and productive life. The discovery of insulin, which began with serendipitous observations, illustrates how unexpected scientific and technological breakthroughs can be supported by carefully planned experiments. It is precisely through such a convergence of circumstances that many hormones were discovered.

In 1889, Oskar Minkowski, a young assistant at the Medical College, and Joseph von Mering of the Hoppe-Seyler Institute in Strasbourg engaged in a friendly debate regarding the role that the pancreas—known to contain lipases—plays in the digestion of fats in dogs. To settle their dispute, the researchers initiated experiments on fat digestion. They surgically removed the pancreas from a dog, and Minkowski noticed that the animal subsequently produced a much greater volume of urine than normal (a common symptom of untreated diabetes). The glucose concentration in the dog's urine was also far above normal (another hallmark of diabetes). These findings indicated that the absence of some pancreatic product leads to the development of diabetes.

Minkowski attempted to reverse the effects of pancreatectomy and lower the glucose concentration in the urine or blood by preparing an extract from a dog's pancreas, but these attempts were unsuccessful... Today, we know that insulin is a protein and that the pancreas is very rich in

proteases (Trypsin and Chymotrypsin) that are normally released into the Small Intestine to digest food. It was precisely these proteases that cleaved insulin in the pancreatic extracts during Minkowski's experiments.

Despite considerable efforts by scientists, no significant progress was made in isolating and identifying the "antidiabetic factor" until the summer of 1921. That year, the challenge was taken up by Frederick G. Banting, a young researcher working in the laboratory of J. J. R. Macleod at the University of Toronto, and his student assistant, Charles Best. Before long, several independent lines of evidence emerged indicating that the source of the antidiabetic factor—named insulin (from Lat. insula, island)—was a specialized group of cells in the pancreas (the islets of Langerhans; see Figs. 23–24).

In December 1921, having taken every precaution to prevent proteolysis, Banting and Best (later joined by biochemist J. B. Collip) succeeded in preparing a purified pancreatic extract that relieved the symptoms of experimentally induced diabetes in dogs. Just a month later, on January 25, 1922, their insulin preparation was administered to Leonard Thompson, a 14-year-old boy severely ill with diabetes. Within a few days, the levels of Ketone Bodies and glucose in Thompson's urine dropped significantly; the extract saved his life. In 1923, Banting and Macleod were awarded the Nobel Prize for the isolation of insulin. Banting immediately announced that he would share his prize with Best, and Macleod shared his with Collip.

By 1923, pharmaceutical companies worldwide were supplying thousands of patients with insulin extracted from the pancreases of pigs.

With the advancement of Recombinant DNA technology in the 1980s (see Ch. 9, Vol. 1), it became possible to produce unlimited quantities of human insulin using microorganisms that were subsequently cultivated on an industrial scale. Today, some diabetes patients use insulin pumps that monitor blood sugar levels and deliver precise amounts of insulin as needed, accommodating the changing demands for the hormone during meals and exercise. Looking to the future, transplantation of pancreatic tissue fragments into diabetic patients holds promise as a source of insulin that would respond like a normal pancreas, releasing insulin into the bloodstream only when blood glucose levels rise.

The key reagent in radioimmunoassay is Antibodies specific to a particular hormone. Purified hormone injected into a rabbit elicits The production of antibodies that bind to that hormone with extremely high affinity and Specificity. When a fixed amount of isolated antibodies is incubated with a known amount of radiolabeled hormone, a specific fraction of the radioactive hormone binds to the antibody (Fig. 23-3). If unlabeled hormone is incubated alongside the radiolabeled hormone, the unlabeled hormone competitively displaces a portion of the labeled hormone from its binding site on the antibody. Based on the concentration at which the labeled hormone is displaced from the antibody, The amount of unlabeled hormone in a blood sample or tissue extract can be calculated. By using an extremely high-specific-activity radiolabeled hormone, the sensitivity of the method can be pushed down to the picogram range. A later modification of this technique is the enzyme-linked immunosorbent assay (ELISA); see Figs. 5-26b, Vol. 1.

Fig. 23-3. Radioimmunoassay (RIA). (a) Low concentrations of radiolabeled hormone (red) were incubated (1) with a fixed amount of antibodies specific for that hormone, or (2) with a fixed amount of antibodies and varying concentrations of unlabeled hormone (blue). In the latter case, the unlabeled hormone competes with the labeled hormone for antibody binding; the amount of bound labeled hormone varies inversely with the concentration of the unlabeled hormone. (b) Radioimmunoassay of adrenocorticotropic hormone (ACTH, or corticotropin). To determine the amount of (unlabeled) ACTH in an unknown sample, a standard curve is plotted as The ratio of bound radiolabeled ACTH to unbound ACTH versus the logarithm of the concentration of added unlabeled hormone. If an aliquot with an unknown amount of unlabeled hormone yields a [bound ACTH]/[unbound ACTH] ratio of 0.4 (indicated by the arrow), that aliquot must contain approximately 10 pg of the hormone.

Hormones Act via Specific, High-Affinity Cellular Receptors

As we saw in Chapter 12 (Vol. 1), all hormones act via highly specific receptors on hormone-responsive target cells, binding hormones with high affinity (see Fig. 12-2, Vol. 1). Each cell type possesses its own unique combination of Hormone Receptors, which dictates its ability to respond to specific hormones. Furthermore, two different cell types bearing identical receptors may possess distinct intracellular targets for hormone action and thus respond differently to the same hormone. The specificity of hormone action is governed by the structural complementarity between the hormone and its receptor; this interaction is highly selective, allowing structurally similar hormones to elicit disparate physiological effects. High affinity for a given hormone enables cells to respond even when hormone concentrations are extremely low. In hormone replacement therapy or pharmacological treatments, it is essential to account for the structural match in specificity and affinity between the drug and the natural hormone to avoid disrupting the delicate physiological balance of the organism. Recall that the receptor-hormone interaction can be quantified using Scatchard analysis (see Box 12-1, Vol. 1), which under optimal conditions allows the calculation of binding affinity (the dissociation constant of the complex) and the number of hormone-binding sites in a receptor preparation.

Depending on the hormone type, the hormone-receptor interaction may take place at the cell surface, in the Cytosol, or within The Nucleus. The intracellular consequences of hormone-receptor interactions can be grouped into at least six major categories: (1) Formation of an intracellular second messenger (such as cAMP or Inositol trisphosphate) that acts as an allosteric regulator of one or more enzymes. (2) Activation of a receptor Tyrosine kinase by an extracellular hormone. (3) Activation of a receptor guanylyl cyclase to produce the second messenger cGMP. (4) Alteration of Membrane Potential resulting from the opening or closing of hormone-regulated Ion Channels. (5) Interaction of a cell-surface adhesion receptor with Extracellular matrix molecules, relaying signals to the Cytoskeleton. (6) Alteration of expression (Introduction/24.html">DNA Transcription into mRNA) of one or more genes by a steroid or steroid-like molecule upon binding to its nuclear receptor protein (see Fig. 12-2, Vol. 1).

Water-soluble peptide and amine hormones (such as insulin and epinephrine) act extracellularly by binding to receptors embedded in The Plasma Membrane of target cells (Fig. 23-4). When a hormone binds to the extracellular domain of the receptor, it induces a conformational change akin to that observed in an allosteric enzyme upon effector binding. This conformational change triggers the downstream cellular effects of the hormone.

A single hormone molecule, upon forming a hormone-receptor complex, activates a catalytic unit that stimulates the production of many second-messenger molecules; thus, the receptor functions not only in signal transmission but also in signal Amplification. The signal may be further amplified through a signaling cascade of sequential steps, wherein each catalyst activates another, resulting in an enormous amplification of the initial signal. A cascade of this type operates in the hormonal Regulation of Glycogen Synthesis and Breakdown by epinephrine (see Fig. 12-7, Vol. 1). Epinephrine (via its receptor) activates adenylyl cyclase, which generates numerous cAMP molecules in response to each hormone molecule bound to a receptor. Cyclic AMP, in turn, activates cAMP-dependent protein kinase (protein kinase A), which activates phosphorylase kinase, which in turn activates Glycogen phosphorylase. The net result is dramatic signal amplification: a single epinephrine molecule triggers The formation of many thousands of glucose-1-phosphate molecules from glycogen.

Fig. 23-4. Two major Mechanisms of Hormone action. Peptide and amine hormones generally elicit faster responses than do steroid and THYROID HORMONES.

Water-insoluble hormones (Steroids, retinoids, and thyroid hormones) readily cross the plasma membrane of their target cells to reach receptor Proteins located in the nucleus (Fig. 23-4). A hallmark of this hormone class is that the hormone-receptor complex itself acts directly as the signal transducer; it interacts with DNA to alter the expression of specific genes, thereby changing the cell's enzymatic profile and, consequently, its metabolism (see Fig. 12-29, Vol. 1).

Hormones that act via Plasma Membrane Receptors typically initiate rapid physiological or biochemical responses. For instance, within seconds of epinephrine release from The adrenal medulla into the bloodstream, accelerated Glycogenolysis is triggered in skeletal muscles. By contrast, thyroid hormones and sex steroids require hours or even days to elicit maximal responses in target tissues. These differences in response times reflect their underlying Mechanisms of action. Rapidly acting hormones generally alter enzymatic activity through allosteric mechanisms or Covalent Modification of pre-existing cellular enzymes. Slowly acting hormones typically alter Gene Expression, leading to the upregulation or downregulation of specific Protein Synthesis.

Hormones Are Chemically Diverse

Mammalian organisms synthesize several classes of hormones that differ markedly in chemical structure and modes of action (Table 23-1). Peptide hormones, Eicosanoids, and amine hormones act extracellularly by binding to cell-surface receptors. Steroids, vitamin D, retinoids, and thyroid hormones cross the plasma membrane and act via nuclear receptors. Nitric oxide also enters the cell, but directly activates a cytosolic enzyme, guanylyl cyclase (see Fig. 12-10, Vol. 1).

Hormones can also be classified based on the pathway traveled from their site of release to target tissues. Endocrine hormones (from Greek endon, within, and krinein, to secrete) are released into the bloodstream and carried throughout the body to target cells (e.g., insulin). Paracrine hormones are secreted into the extracellular fluid and diffuse to neighboring target cells (e.g., eicosanoids). Autocrine hormones are released by the very cells upon which they act, binding to cell-surface receptors on the same cells.

Mammals possess a remarkably sophisticated hormonal signaling system. However, insects and nematodes also possess highly developed regulatory endocrine systems, with mechanisms that closely mirror those found in mammals. Plants similarly utilize hormonal signals to coordinate enzymatic activities across different tissues (Ch. 12). Although research on Plant Hormones has progressed less rapidly than that of animal hormones, it is now clear that many underlying mechanisms are shared. To illustrate the structural diversity and mechanisms of action of mammalian hormones, we will examine representative Examples from each hormone class (Table 23-1).

Table 23-1. Classes of Hormones

Peptide Hormones. Peptide hormones can range in size from 3 to 200 or more amino acid residues. This group includes the Pancreatic Hormones insulin, glucagon, and Somatostatin, the parathyroid hormone Calcitonin, and all the Hormones of the Hypothalamus and Pituitary gland (see below). These hormones are synthesized on Ribosomes as large precursor proteins (prohormones), packaged into secretory vesicles, and proteolytically processed to yield the active Peptides. Insulin is a small protein ($M_r$ 5,800) composed of two polypeptide chains, A and B, linked by two Disulfide Bonds. The pancreas synthesizes an inactive single-chain precursor, preproinsulin (Fig. 23-5), featuring an N-terminal signal sequence that directs it into secretory vesicles. (Signal sequences are discussed in Chapter 27; see Fig. 27-38, Vol. 3.) Proteolytic removal of the signal sequence and the formation of three disulfide bonds yield proinsulin, which is stored in secretory granules of pancreatic $eta$-cells. Upon stimulation of insulin secretion by elevated glucose levels, stored proinsulin is converted into active insulin by specific proteases that cleave two peptide bonds, producing the mature insulin molecule.

Fig. 23-5. Insulin. Mature insulin is generated from its precursor macromolecule, preproinsulin, via proteolytic Processing. Proinsulin is formed by removing a 23-amino-acid segment (the signal sequence) from the N-terminus of preproinsulin and establishing three disulfide bonds. Subsequent proteolytic Cleavage removes the C-peptide from proinsulin, yielding mature insulin, which consists of A and B chains. The Amino Acid Sequence of bovine insulin is shown in Fig. 3-24, Vol. 1.

Much more frequently, rather than yielding a single large peptide hormone, a prohormone protein is cleaved to produce multiple active hormones. A striking example of multiple hormones encoded by a single gene is pro-opiomelanocortin (POMC). The POMC gene encodes a large polypeptide that is sequentially cleaved into at least nine biologically active peptides (Fig. 23-6). The terminal residues of peptide hormones are very frequently modified, as is the case for TRH (Fig. 23-2), for instance.

Fig. 23-6. Proteolytic Processing of the pro-opiomelanocortin (POMC) precursor. The primary gene product of POMC is a long polypeptide that undergoes cleavage by a series of proteases. This yields ACTH, β- and γ-lipotropins, α-, β-, and γ-MSH (melanocyte-stimulating hormones), CLIP (corticotropin-like intermediate lobe peptide), β-endorphin, and Met-enkephalin. The cleavage sites occur between pairs of basic amino acid residues such as Arg-Lys, Lys-Arg, and Lys-Kerala.

The concentration of peptide hormones within secretory granules is so high that the vesicular contents are nearly crystalline; consequently, when these granules are released via exocytosis, a massive amount of hormone appears instantly. Endocrine glands that produce peptides are surrounded by fenestrated capillaries (which are permeable to peptides), allowing hormone molecules to readily enter the bloodstream and be transported to target cells throughout the body. As noted earlier, all peptide hormones act by binding to receptors on the plasma membrane. This interaction triggers a second messenger that enters the cytosol, alters The activity of a specific intracellular enzyme, and thereby modifies overall cellular metabolism.

Catecholamine hormones. The water-soluble substances epinephrine and norepinephrine are classified as catecholamines due to their structural similarity to catechol. They are synthesized from tyrosine.

Tyrosine -> L-Dopa -> Dopamine -> Norepinephrine -> Epinephrine

Catecholamines produced in the brain and other Tissues of the nervous system act as neurotransmitters. However, the hormones epinephrine and norepinephrine are synthesized and secreted by the Adrenal Glands. Like peptide hormones, catecholamines are stored within secretory vesicles at very high concentrations and are released via exocytosis. They act by binding to cell-surface receptors, which triggers the generation of intracellular second messengers. Catecholamines mediate A wide variety of physiological responses to acute stress (see Table 23-6).

Eicosanoid hormones (Prostaglandins, thromboxanes, Leukotrienes) are derived from arachidonic acid (a 20-carbon polyunsaturated fatty acid).

Unlike the hormones discussed above, they are not synthesized in advance and stored; rather, they are produced only on demand. Eicosanoid hormones are generated from arachidonic acid, which is released from membrane Phospholipids through the enzymatic activity of phospholipase A₂ (see Fig. 10-18, Vol. 1).

Enzymes involved in The Biosynthesis of Prostaglandins and thromboxanes are widespread in mammalian tissues (see Fig. 21-15). Most cells are capable of synthesizing and signaling via eicosanoids, and cells in many tissues can respond to these signals by activating specific plasma membrane receptors. Paracrine eicosanoid hormones are secreted into the tissue fluid (and occasionally into the blood) to act on neighboring cells.

Prostaglandins stimulate smooth Muscle contraction, including that of the intestine and Uterus (making them useful for inducing labor during childbirth). Eicosanoids also serve to alleviate pain and inflammation across various tissues. Many anti-inflammatory drugs exert their effects by inhibiting specific steps in prostaglandin synthesis (see Fig. 21-5). Thromboxanes regulate platelet function and thereby influence blood clotting. Leukotrienes LTC₄ and LTD₄ bind to plasma membrane receptors, inducing contractions of the smooth muscle in the intestines, Bronchi, and Trachea. They mediate anaphylactic Shock, a severe and adverse Immune Response. ■

Steroid Hormones (adrenocorticoids and Sex Hormones) are synthesized from Cholesterol by several endocrine glands.

Bound to carrier proteins, they are transported via the bloodstream to target cells. The adrenal cortex produces more than 50 corticosteroid hormones; enzymatic reactions remove the side chain from the D-ring of cholesterol and introduce oxygen atoms to form keto and hydroxyl groups. Many of these reactions involve cytochrome P-450-containing enzymes (see Box 21-1). There are two MAIN TYPES OF steroid hormones. Glucocorticoids (such as cortisol) primarily affect Carbohydrate Metabolism, whereas mineralocorticoids (such as aldosterone) regulate blood electrolyte concentrations. The Testes and Ovaries synthesize androgens (testosterone) and estrogens (such as estradiol, see Fig. 10-19, Vol. 1). Their synthesis relies on cytochrome P-450-containing enzymes, which cleave the cholesterol side chain and attach oxygen atoms. Androgens and estrogens govern sexual development, reproductive behavior, and numerous other physiological functions, both reproductive and non-reproductive.

All steroid hormones bind to nuclear receptors to alter the expression of specific genes (p. 643, Vol. 1). They can also act more rapidly via receptors located on the plasma membrane.

Vitamin D hormone. Calcitriol (1,25-dihydroxycholecalciferol) is produced in the liver and Kidneys from vitamin D via enzymatic hydroxylation (Fig. 10-20a, Vol. 1). The body obtains vitamin D from dietary sources or through the photolysis of 7-dehydrocholesterol in the Skin upon exposure to sunlight.

Calcitriol participates in Ca²⁺ Homeostasis alongside parathyroid hormone, regulating blood calcium ion concentrations and the balance between stored Ca²⁺ and Ca²⁺ mobilized from bone. Acting via nuclear receptors, calcitriol stimulates the synthesis of a intestinal Ca²⁺-binding protein, which is essential for the absorption of dietary Ca²⁺. Inadequate Dietary intake of vitamin D or defects in calcitriol biosynthesis lead to severe disorders such as Rickets, in which bones become weakened and deformed (Fig. 10-20b, Vol. 1). ■

Retinoid hormones. Retinoids are potent hormones that regulate cell growth and differentiation through nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, predominantly in the liver (see Fig. 10-21, Vol. 1); in many tissues, retinol is converted into retinoic acid.

Retinoic acid affects virtually all tissues because every cell type possesses at least one form of nuclear retinoid receptor. In adults, the primary targets include the cornea, skin, lung and tracheal epithelium, and The Immune System. Retinoic acid regulates the synthesis of proteins critical for cell growth and differentiation. Excess vitamin A can cause birth defects; consequently, pregnant women are advised to avoid retinoid-containing creams intended for severe acne Treatment. ■

Thyroid hormones. Thyroid hormones T₄ (thyroxine) and T₃ (triiodothyronine) are synthesized from the precursor protein thyroglobulin (Mr 660,000). Within The Thyroid Gland, more than 20 tyrosine residues in the thyroglobulin molecule are enzymatically iodinated. Two iodotyrosine residues then couple to form the hormone thyroxine. When needed, it is released through proteolysis. Monoiodotyrosine coupling with diiodotyrosine yields the active hormone T₃, which is also released via proteolysis.

Thyroid hormones act via nuclear receptors to stimulate energy metabolism, particularly in the liver and muscles, thereby upregulating the expression of genes encoding key catabolic enzymes.

Nitric oxide (NO). Nitric oxide is a relatively stable free radical synthesized from molecular oxygen and the guanidino nitrogen of Arginine (Fig. 22-31) in a reaction catalyzed by NO synthase.

Arginine + 1¹/₂ NАDРН +2 O₂ —> NO + citrulline + 2 Н₂O + 1¹/₂ NАDР⁺

This enzyme is found in numerous tissues and diverse cell types, including Neurons, macrophages, hepatocytes, smooth muscle myocytes, and the endothelial cells of Blood Vessels and kidneys. NO acts in the immediate vicinity of its release, diffusing into target cells where it activates cytoplasmic guanylyl cyclase, an enzyme that catalyzes the synthesis of The secondary messenger cGMP (see Fig. 12-20, Vol. 1).

Hormone release is regulated hierarchically by neuronal and hormonal signals

While fluctuations in hormone concentrations regulate cellular processes, what governs the levels of the hormones themselves? This responsibility falls to the Central Nervous System (CNS), which integrates signals regarding danger, hunger, food intake, and blood composition and pressure gathered by numerous internal and external sensors, and subsequently orchestrates the secretion of appropriate hormones by endocrine glands. To explore this in greater detail, let us examine the principal human hormonal systems and their functional interrelationships.

Figure 23-7 illustrates the anatomical locations of the major human endocrine glands, and Figure 23-8 depicts the "command chain" within the hierarchy of hormonal signaling. The coordination center of the endocrine system is the hypothalamus, a small region of the brain (Fig. 23-9) that receives and integrates messages from the central nervous system. In response to CNS signals, the hypothalamus produces regulatory hormones (releasing factors) that travel directly to the adjacent Pituitary Gland via specialized blood vessels and neurons connecting the two structures (Fig. 23-9, b). The pituitary gland consists of two functionally distinct lobes. The posterior pituitary contains the axon terminals of numerous neurons whose cell bodies reside in the hypothalamus. These neurons synthesize the short peptide hormones oxytocin and vasopressin (Fig. 23-10), which are transported down the axons to nerve endings in the pituitary, where they are stored in secretory granules awaiting the signal for release.

Figure 23-7. The major endocrine glands. Glands are highlighted in red.

The anterior pituitary responds to blood-borne hypothalamic hormones by producing tropic hormones, or tropins (from the Greek tropos, meaning "turn"). These relatively long Polypeptides stimulate a variety of endocrine glands (Fig. 23-8), including the adrenal cortex, thyroid, ovaries, and testes. In response, these target glands secrete their own specific hormones, which are carried via the bloodstream to cellular receptors in target tissues. For instance, hypothalamic corticotropin-releasing hormone stimulates the release of ACTH by the anterior pituitary, and ACTH travels to the zona fasciculata of the adrenal cortex to trigger the release of cortisol. Cortisol, the final hormone in this cascade, acts through its receptors to alter metabolism in various target cell types. One of cortisol's effects in hepatocytes is an increased rate of Gluconeogenesis.

Figure 23-8. Major endocrine systems and their target tissues. Signals originating in the central nervous system (top) pass through a series of cascades to the ultimate target tissues (bottom). In addition to the glands shown in the diagram, hormones are also secreted by the Thymus, Pineal Gland, and groups of cells within the gastrointestinal tract. Dashed lines indicate connections within the CNS.

Figure 23-9. Neuroendocrine origin of hormonal signals. (a) Anatomic Location OF THE hypothalamus and pituitary gland. (b) The hypothalamo-pituitary system. Interneuronal signals from the hypothalamus to the pituitary stimulate the hypothalamic secretion of releasing factors into the bloodstream, which delivers these hormones directly to the capillary network of the anterior pituitary. In response to each hypothalamic releasing factor, the anterior pituitary releases its corresponding hormone into the Circulatory system. The hormones of the posterior pituitary are synthesized in neurons originating in the hypothalamus; these hormones are transported along axons to nerve endings in the posterior pituitary, where they are stored until released into the blood in response to a Nerve Impulse.

Figure 23-10. The two hormones of the posterior pituitary. The C-termini of both peptides feature a glycinamide residue, -NH-CH₂-CONH₂ (C-terminal amidation is a common feature of short peptide hormones; see Fig. 23-2). Except for two amino acid residues (highlighted in pink), these two hormones are identical in composition, yet they elicit markedly different biological effects. Oxytocin acts on the smooth muscle of the uterus and the Mammary Glands, inducing uterine contractions during childbirth and milk ejection during Lactation. Vasopressin (antidiuretic hormone) enhances water reabsorption in the kidneys and causes blood vessel constriction, thereby elevating blood pressure.

The hormonal cascades leading to the release of cortisol and epinephrine achieve substantial amplification of the initial signal, allowing for exceptionally fine and precise Regulation of the final hormone's output (Fig. 23-11). At each level of the cascade, a "small" signal is amplified into a larger response. An initial electrical impulse arriving at the hypothalamus triggers the release of a few nanograms of corticotropin-releasing hormone, which amplifies the signal to yield the release of several micrograms of corticotropin. Corticotropin then acts on the adrenal cortex to stimulate the secretion of several milligrams of cortisol, resulting in a signal amplification of at least a million-fold.

Figure 23-11. The hormone release cascade triggered by a central nervous system impulse to the hypothalamus. At each endocrine gland, the signal from the preceding level is received and amplified, prompting the release of the next hormone in the cascade. At multiple levels, the cascade is subject to feedback regulation via inhibition by the final hormone (as in the case of cortisol). In other words, the product regulates its own production, much like feedback inhibition operates in intracellular biosynthesis pathways.

Feedback inhibition of early stages can occur at any level of the hormonal cascade: an excess concentration of the final hormone or any of the intermediate hormones inhibits the release of preceding hormones in the cascade. Here, the feedback mechanism achieves the same outcome as the product-limiting mechanisms in biosynthetic pathways (compare Fig. 23-11 and Fig. 6-28, Vol. 1): the product is synthesized (or released) only until the required concentration is attained.

Summary of Section 23.1 Hormones: Diverse Structures for Diverse Functions

■ Hormones are chemical messengers secreted by specific tissues into the blood or extracellular fluid, serving to regulate the activity of other cells or tissues.

■ Radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) are highly sensitive methods for detecting and quantifying hormone levels.

■ Peptide hormones, eicosanoid hormones, and amino acid-derived hormones act on the exterior of target cells by binding to specific plasma membrane receptors, thereby altering the intracellular concentration of a second messenger.

■ Steroid hormones, retinoid hormones, vitamin D, and thyroid hormones penetrate target cells and interact with specific nuclear receptors.

■ Hormonal cascades, in which a catalyst activates another catalyst, amplify the initial stimulus several-fold, often within a very short timeframe (seconds).

■ Nerve impulses stimulate the hypothalamus to release specific hormones to the pituitary gland, thereby stimulating (or inhibiting) the release of tropic hormones. These hormones, in turn, stimulate other endocrine glands (the thyroid, adrenal glands, and pancreas) to secrete their own hormones, which then act upon target tissues.