23.1 Hormone Structure and Action in Chapter 23 Hormonal Regulation and Integration of Mammalian Metabolism

23.1 Hormone Structure and Action

Hormones are small molecules or proteins that are produced in one tissue, released into the bloodstream, and carried to other tissues, where they act through specific receptors to bring about changes in cellular activities. Hormones serve to coordinate the metabolic activities of several tissues or organs. Virtually every process in a complex organism is regulated by one or more hormones: maintenance of blood pressure, blood volume, and electrolyte balance; embryogenesis; sexual differentiation, development, and reproduction; hunger, eating behavior, digestion, and fuel allocation — to name but a few.

The coordination of metabolism in mammals is achieved by the neuroendocrine system. Individual cells in one tissue sense a change in the organism’s circumstances and respond by secreting a chemical messenger that passes to another cell in the same or different tissue, where the messenger binds to a specific receptor molecule and triggers a change in this target cell. These chemical messengers may relay information over very short or very long distances. In neuronal signaling (Fig. 23-1a), the chemical messenger is a neurotransmitter (acetylcholine, for example) that may travel only a fraction of a micrometer across a synaptic cleft to the next neuron in a network. In endocrine signaling (Fig. 23-1b), the messenger is a hormone that is carried in the bloodstream to neighboring cells or to distant organs and tissues; it may travel a meter or more before encountering its target cell. Except for this anatomic difference, the neuronal and endocrine signaling mechanisms are remarkably similar, and the same molecule can sometimes act as both neurotransmitter and hormone. Epinephrine and norepinephrine, for example, serve as neurotransmitters at certain synapses of the brain and at neuromuscular junctions of smooth muscle and as hormones that regulate fuel metabolism in liver and muscle. The following discussion of cellular signaling emphasizes hormone action, drawing on discussions of fuel metabolism in earlier chapters, but most of the fundamental mechanisms described here also occur in neurotransmitter action.

A two-part figure shows signaling by the neuroendocrine system by showing neuronal signaling in part a and endocrine signaling in part b. — FIGURE 23-1 Signaling by the neuroendocrine system. (a) In neuronal signaling, electrical signals (nerve impulses) originate in the cell body of a neuron and travel very rapidly over long distances to the axon tip, where neurotransmitters are released and diffuse to the target cell. The target cell (another neuron, a myocyte, or a secretory cell) is only a fraction of a micrometer or a few micrometers away from the site of neurotransmitter release. (b) In endocrine signaling, hormones (such as insulin produced in pancreatic β cells) are secreted into the bloodstream, which carries 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 or in their target cells, triggering responses.

The figure has a square central portion with a horizontal line that separates a smaller top portion from a larger bottom portion. Signaling distance is labeled along the left vertical side of this square and brackets indicate that the distance of the top portion is in micrometers and the distance of the bottom portion is in c m to m. In part a, labeled neuronal signaling, a neuron is shown at the top center with a cell body containing a nucleus, many dendrites extending to the sides and top, and an axon extending vertically downward accompanied by a downward arrow labeled, nerve impulse. The axon divides into two portions. The left half further divides into three parts that extend to target cells. These ends further divide into two of three smaller stands at the very ends. At the end of each of these linear strands, there are small blue spheres labeled neurotransmitters between the end of the terminal portion extending from the axon and the target cells below. From left to right, neurotransmitters are shown being released between two strands on the left and a neuron, between the third strand and the top of a fusiform muscle, and from the right-hand strand and a layer of three cells. The boundary between the smaller top and larger bottom portions of the square runs through the center of the neuron, muscle, and layer of cells. An arrow pointing downward along an axon from the neuron is labeled nerve impulse. The fusiform muscle is labeled with the word contraction beneath. The layer of three cells to the right have thicker bottom membranes, nuclei, vesicles near the top surfaces, and irregular top surfaces. Arrows point up from the top surface of each cell and text below reads secretion. Part b, labeled endocrine signaling, shows a blood vessel that curves from the lower left of the square to end at the right end of the square just below half the vertical height of the square. Beneath the square, the endocrine pancreas is shown as a tan organ with many small, roughly round pieces joined together to make a long piece across the top that narrows to the upper right and a wider left side that bends down and folds back toward the right. Three red squares and three blue triangles are shown in the pancreas with an arrow pointing up to show them entering the bloodstream, shown as pink material inside the blood vessel. The bloodstream contains many of these red squares and blue triangles, which are labeled hormones. An arrow points up from the center of the blood vessel to a blue triangle just beneath the fusiform muscle cell and the word contraction. Near the right end of the blood vessel, an arrow points up to a red square beneath the layer of three cells and the word secretion. Between the arrows to the muscle and the layer of three cells, two arrows point downward to two blue triangles between the blood vessel and a layer of target cells below. Text between the blood vessel and target cells reads, metabolic change.

Hormones Act through Specific High-Affinity Cellular Receptors

Hormones exert their effects through specific receptors in target cells. The high affinity of the hormone-receptor interaction allows cells to respond to very low concentrations of hormone. Recall from Chapter 12 (Fig. 12-2) that there are four general types of intracellular consequences of ligand-receptor interaction: (1) a second messenger, such as cAMP, cGMP, or inositol trisphosphate, generated inside the cell, acts as an allosteric regulator of one or more enzymes; (2) a receptor tyrosine kinase is activated by the extracellular hormone; (3) a change in membrane potential results from the opening or closing of a hormone-gated ion channel; and (4) a steroid or steroidlike molecule causes a change in the level of expression (transcription of DNA into mRNA) of one or more genes, mediated by a nuclear hormone receptor protein. It can be helpful to characterize cell surface hormone receptors as metabotropic, those that activate or inhibit an enzyme downstream from the receptor, or ionotropic, those that open or close an ion channel in the plasma membrane, resulting in a change in membrane potential $(Δ V_{m})$ $left-parenthesis upper Delta upper V Subscript m Baseline right-parenthesis$ or in the concentration of an ion such as ${Ca}^{2 +}$ $Ca Superscript 2 plus$ (Fig. 23-2).

A figure shows two general mechanisms of hormone action, one involving the action of peptide hormones and the other involving the action of steroid and thyroid hormones. — FIGURE 23-2 Two general mechanisms of hormone action. The peptide and amine hormones are faster-acting than steroid and thyroid hormones. Peptide hormones act from outside the cell, binding a plasma membrane hormone receptor. Steroid and thyroid hormones pass through the plasma membrane and enter the nucleus, where they regulate the expression of specific genes.

A horizontal layer of cell membrane runs across the illustration just above halfway up its vertical axis. Two receptors are shown embedded vertically in the left half of the membrane. Text above reads, Cell surface receptor with a box below that reads, Peptide or amine hormone binds to receptor on the outside of the cell; acts through receptor without entering the cell. The left-hand receptor is labeled, metabotropic. A roughly rectangular vertical receptor that is taller on its right side versus its left side has a cutout in its top half above the membrane. A brown hormone is shown above with an oval base that connects to a hexagonal piece on the right. A curved arrow points down to show that this hormone fits into the cutout in the left-hand receptor, A curved arrow bends up across the bottom of the receptor, beneath he membrane, then points down to text reading, second messenger (e.g., c A M P). From here, two arrows point away: an arrow points down to text reading, altered activity of preexisting enzyme and an arrow points right across the nuclear envelope to text reading, altered transcription of specific genes. An arrow points down from altered transcription of specific genes through the nuclear membrane to text below reading, altered amount of newly synthesized proteins. The middle receptor in the cell membrane is labeled ionotropic above text reading, N a plus, K plus, C a 2 plus. This receptor is cylindrical with a tubular appearance, providing a central passageway. A green hormone with an oval base that connects to a hexagonal piece is shown attached to the upper left side of the receptor above the membrane. An arrow points down from N a plus, K plus, C a 2 plus through the receptor to N a plus, K plus, C a 2 plus within the membrane. A second arrow points down from these ions to text reading, delta V subscript lowercase m end lowercase. The right-hand receptor is beneath text above that reads, Nuclear receptor with a box below that reads, Steroid or thyroid hormone enters the cell; hormone-receptor complex acts in the nucleus. A red hormone resembling the bottom half of an oval is shown above the plasma membrane and an arrow points down from this hormone through the nuclear membrane into the nucleus. A green structure with an oval half joined with a crescent-shape on the right, providing a rounded opening at the upper left, has an arrow that joins with the arrow from the hormone to point to a structure consisting of the green structure with the red hormone fitted into the rounded opening positioned above a tan structure with a passageway through its center containing a horizontal blue double helix of D N A that bends as its passes through the structure. Text below reads, altered transcription of specific genes. Another arrow points down through the nuclear envelope to text in the cytoplasm reading, altered amount of newly synthesized proteins.

A single hormone molecule, in forming a hormone-receptor complex, activates a catalyst that produces many molecules of second messenger, so the receptor serves as both signal transducer and signal amplifier. The signal may be further amplified by a signaling cascade, such as we saw in the regulation of glycogen synthesis and breakdown by epinephrine (see Fig. 12-7). Signal amplification allows one epinephrine molecule to result in the production of many thousands or millions of molecules of glucose 1-phosphate from glycogen.

Water-insoluble hormones, including the steroid, retinoid, and thyroid hormones, readily pass through the plasma membrane of their target cells to reach their receptor proteins in the nucleus (Fig. 23-2). The hormone-receptor complex itself carries the message: it interacts with DNA to alter the expression of specific genes, changing the enzyme content of the cell and thereby changing cellular metabolism (see Fig. 12-34).

Hormones that act through plasma membrane receptors generally trigger very rapid physiological or biochemical responses. Just seconds after the adrenal medulla secretes epinephrine into the bloodstream, skeletal muscle responds by accelerating the breakdown of glycogen. By contrast, the thyroid hormones and the sex (steroid) hormones promote maximal responses in their target tissues only after hours or even days. These differences in response time correspond to different modes of action. In general, the fast-acting hormones lead to a change in the activity of one or more preexisting enzymes in the cell, by allosteric mechanisms or covalent modification. The slower-acting hormones generally alter gene expression, resulting in the synthesis of more (upregulation) or less (downregulation) of the regulated protein(s).

Hormones Are Chemically Diverse

Mammals have several classes of hormones, distinguishable by their diverse chemical structures and their modes of action (Table 23-1). Peptide, catecholamine, eicosanoid, and endocannabinoid hormones act from outside the target cell via cell surface receptors. Steroid, vitamin D, retinoid, and thyroid hormones enter the cell and act through nuclear receptors. Nitric oxide (a gas) also enters the cell, but activates a cytosolic enzyme, guanylyl cyclase.

TABLE 23-1 Classes of Hormones

Column headings: Type; Example; Synthetic path; Mode of action. Row 1: Protein; Insulin (Figure 23-4); Proteolytic processing of prohormone; Plasma membrane R T K. Row 2: Protein; Glucagon; Proteolytic processing of prohormone; Plasma membrane G P C R s, second messengers. Row 3: Peptide; Vasopressin (page 880); Proteolytic processing of prohormone; Plasma membrane G P C R s, second messengers. Row 4: Catecholamine; Epinephrine (Figure 22-31); From tyrosine; Plasma membrane G P C R s, second messengers. Row 5: Eicosanoid; Prostaglandin E subscript 2 (Figure 10-17); From arachidonate; Plasma membrane G P C R s, second messengers. Row 6: Endocannabinoid; Anandamide (Figure 23-40); From arachidonate; Plasma membrane G P C R s, second messengers. Row 7: Steroid; Testosterone (Figure 10-18); From cholesterol; Nuclear receptors, transcriptional regulation. Row 8: Corticosteroid; Cortisol (Figure 10-18); From cholesterol; Nuclear receptors, transcriptional regulation. Row 9: Vitamin D; Calcitriol (Figure 10-19); From cholesterol; Nuclear receptors, transcriptional regulation. Row 10: Retinoid; Retinoic acid (Figure 10-20); From vitamin A; Nuclear receptors, transcriptional regulation. Row 11: Thyroid; Triiodothyronine (T subscript 3); From T y r in thyroglobulin; Nuclear receptors, transcriptional regulation. Row 12: Nitric oxide; N O radical (Figure 22-33); From arginine; Cytosolic receptor, second messenger.

Hormones can also be classified by the way they get from their point of release to their target tissue. Endocrine (from the Greek endon, “within,” and krinein, “to release”) hormones are released into the blood and carried to target cells throughout the body (insulin and glucagon are examples). Paracrine hormones are released into the extracellular space and diffuse to neighboring target cells (the eicosanoid hormones are of this type). Autocrine hormones affect the same cell that releases them, binding to receptors on the cell surface.

The peptide hormones vary in size from 3 (thyrotropin-releasing hormone; Fig. 23-3) to more than 200 (human chorionic gonadotropin) amino acid residues. They include the pancreatic hormones insulin, glucagon, and somatostatin; the parathyroid hormone calcitonin; and all the hormones of the hypothalamus and pituitary. Peptide hormones (some of which are actually small proteins) are synthesized as proproteins (prohormones) that are activated upon release by proteolytic cleavage, much as we saw with zymogen activation of pancreatic enzymes (Fig. 6-42) and the blood-clotting cascade (Fig. 6-44). In some cases, a preproprotein is synthesized and processed to create more than one active peptide product.

A figure shows the structure of thyrotropin-releasing hormone (T R H), which is a derivative of G l u – H i s – P r o. — FIGURE 23-3 The structure of thyrotropin-releasing hormone (TRH). Purified (through heroic efforts) from extracts of hypothalamus, TRH proved to be a derivative of the tripeptide Glu–His–Pro. The side-chain carboxyl group of the amino-terminal Glu forms an amide (red bond) with the residue’s α-amino group, creating pyroglutamate, and the carboxyl group of the carboxyl-terminal Pro is converted to an amide (red $— {NH}_{2}$ $em-dash NH Subscript 2 Baseline$ ). Such modifications are common among the small peptide hormones. In a typical protein of $upper M Subscript r Baseline tilde 50 comma 000$ $upper M Subscript r Baseline tilde 50 comma 000$ , the charges on the amino- and carboxyl-terminal groups contribute relatively little to the overall charge on the molecule, but in a tripeptide these two charges dominate the properties of the molecule. Formation of the amide derivatives removes these charges.

FIGURE 23-3 The structure of thyrotropin-releasing hormone (TRH). Purified (through heroic efforts) from extracts of hypothalamus, TRH proved to be a derivative of the tripeptide Glu–His–Pro. The side-chain carboxyl group of the amino-terminal Glu forms an amide (red bond) with the residue’s α-amino group, creating pyroglutamate, and the carboxyl group of the carboxyl-terminal Pro is converted to an amide (red $— {NH}_{2}$ $em-dash NH Subscript 2 Baseline$ ). Such modifications are common among the small peptide hormones. In a typical protein of $upper M Subscript r Baseline tilde 50 comma 000$ $upper M Subscript r Baseline tilde 50 comma 000$ , the charges on the amino- and carboxyl-terminal groups contribute relatively little to the overall charge on the molecule, but in a tripeptide these two charges dominate the properties of the molecule. Formation of the amide derivatives removes these charges.

A figure shows three amino acids joined together. Bolded text beneath reads, pyro-G l u – H i s – P r o – N H 2. The left-hand structure is labeled pyroglutamate, the central amino acid is labeled histidine, and the right-hand structure is labeled prolyamide. From left to right, the structure is as follows with dashed vertical lines separating the three components. A five-membered ring has N H at the lower left vertex, C at the upper left vertex double bonded to O to the left, C H 2 at the top vertex, C H 2 at the upper right vertex, and C H at the lower right vertex further bonded to C double bonded to O above and connected by a bond bisected by a dashed vertical line to N H that begins histidine. This N H is bonded to C H that is bonded below and to the right. This C H is bonded below to C H bonded to C at the upper left vertex of a five-membered ring with N H at the upper right vertex, double bonds at its lower right and left sides, C H at the right side vertex, N at the lower right vertex, and C H at the lower left vertex. To the right, the central C H of histidine is bonded to C double bonded to O above and further connected by a bond bisected by a dashed vertical line to the N that begins prolylamide. This N forms the lower left vertex of a five-membered ring with C H 2 at the upper left vertex, top vertex, and upper right vertex and with C H at the lower right vertex further bonded to C that is double bonded to O to the upper right and connected by a red bond to red highlighted N H 2 to the lower right.

Insulin is a small protein ( $M_{r}$ $upper M Subscript r$ 5,800) with two polypeptide chains, A and B, joined by two disulfide bonds. (The amino acid sequence of bovine insulin is shown in Figure 3-24.) It is synthesized in the pancreas as an inactive single-chain precursor, preproinsulin (Fig. 23-4), with an amino-terminal “signal sequence” that directs its passage into secretory vesicles. (Signal sequences are discussed in Chapter 27; see Fig. 27-38.) Proteolytic removal of the signal sequence and formation of three disulfide bonds produces proinsulin, which is stored in secretory granules in pancreatic β cells. When blood glucose is elevated sufficiently to trigger insulin secretion, proinsulin is converted to active insulin by specific proteases, which cleave two peptide bonds to form the mature insulin molecule and C peptide, which are released into the blood by exocytosis. The capillaries that serve peptide-producing endocrine glands are fenestrated (punctuated with tiny holes or “windows”), so the hormone molecules readily enter the bloodstream for transport to target cells elsewhere. Insulin, acting through its receptor tyrosine kinase (Fig. 12-21) has profound effects on both anabolic and catabolic processes in many tissues, which we explore in detail below.

A figure shows how mature insulin is formed from preproinsulin, a larger precursor molecule. — FIGURE 23-4 Insulin. Mature insulin is formed from its larger precursor preproinsulin by proteolytic processing. Removal of a 23 amino acid segment (the signal sequence) at the amino terminus of preproinsulin and formation of three disulfide bonds produce proinsulin. Further proteolytic cuts remove the C peptide from proinsulin to produce mature insulin, composed of A and B chains.

Preproinsulin is shown as a curved stand that begins with an orange signal sequence at the upper left that is bonded to N H 3 with a positive charge on N to the left. To the right, the signal sequence is joined with a long segment labeled B. Segment B has yellow bonds to S H in yellow boxes located at its far left, just before the orange signal sequence, and about halfway across the length of the top horizontal piece of segment B. Segment B curves down slightly to the right before joining dark purple segment C, which runs down and then curves to the left to run just to the left of the start of the signal sequence above before curving upward to meet a pale purple sequence labeled A. Sequence A extends right to about three-quarters of the way across the entire structure. It has yellow bonds to S H in yellow boxes located above and below its left side, vertically beneath the left-hand S H of segment B above, a yellow bond to S H that extends below slightly to the right of these two, and a yellow box to S H in a yellow box near its right end that extends up and is vertically aligned with the right-hand S H of segment B. Segment A ends with a bond to C O O minus. An arrow points down with a curved arrow branching off to show the loss of the signal sequence. This yields proinsulin, which is similar in structure to preproinsulin except that the signal sequence is missing, the left-hand end of segment B ends with a bond to N H 3 with a positive charge on N, and the yellow S H groups have formed bonds. There is a bond from the S extending down near the left end of segment B to the S extending up near the left side of segment A in the middle, from the S extending down about halfway across segment B to the S extending up from the right side of segment A, and horizontally between the two S extending down near the left end of segment A. All of these S atoms and related bonds are enclosed in yellow. An arrow points downward with a curved arrow branching off to show the loss of the dark purple C peptide. This yields mature insulin, which has the same blue (B chain) and light purple (A chain) pieces as before with the same bonds between S atoms chains are before. However, the dark purple C peptide no longer joins the B and A chains by running from the lower right across the bottom and up to meet the lower left side of the A chain.

Pro-opiomelanocortin (POMC) is a spectacular example of a proprotein that undergoes specific cleavage to produce several active hormones. The POMC gene encodes a large polypeptide that contains within it at least nine biologically active peptides (Fig. 23-5). The proprotein is processed differently in different tissues, depending on which proteases the cells express. The active products influence an astonishing number of physiological systems.

A figure shows the proteolytic processing of the pro-opiomelanocortin (P O M C) precursor. — FIGURE 23-5 Proteolytic processing of the pro-opiomelanocortin (POMC) precursor. The initial gene product of the POMC gene is a long polypeptide that undergoes cleavage by a series of specific proteases to produce ACTH (corticotropin), β- and γ-lipotropin, α-, β-, and γ-MSH (melanocyte-stimulating hormone, or melanocortin), CLIP (corticotropin-like intermediary peptide), β-endorphin, and Met-enkephalin. The points of cleavage are pairs of basic residues, Arg–Lys, Lys–Arg, or Lys–Lys.

A horizontal strand of D N A is light blue with a central darker blue region labeled pro-opiomelanocortin (P O M C) gene. An arrow points down to show a dark green strand of m R N A the length of the P O M C gene with its 5 prime end on the left and its 3 prime end on the right. An arrow points down to show a polypeptide with an orange signal peptide on the left bonded to N H 3 on the left with a positive charge on N. From left to right, the peptide consists of segments that are all relatively similar in size as follows: slightly larger signal peptide, light green segment, orange segment, purple segment, light purple segment, light blue segment, pale bluish white segment, slightly smaller blue segment, very small purplish blue segment, and long light blue segment that ends with a bond to C O O minus. Three arrows point downward to a horizontal row of segments as follows. An arrow points down from the light green segment to a similar segment labeled gamma-M S H. An arrow points down from the dark purple segment next to a light purple segment to a similar pair of segments labeled A C T H. An arrow points down from the remaining portion of the molecule to the right of the light purple segment to a similar segment labeled beta-lipotropin. Two arrows point down to a horizontal row of segments as follows. An arrow from A C T H points to a similar dark purple piece labeled alpha M S H and a similar light purple piece labeled C L I P. An arrow pointing down from the left end of beta-lipotropin points down to a similar light blue segment next to a pale bluish white segment labeled gamma-lipotropin. A very small purplish blue segment next to a light blue segment resembling the right end of beta-lipotropin is labeled beta-endorphin. Two arrows point down to a horizontal row of two segments as follows. An arrow points down from gamma-lipotropin to a similar light bluish white segment labeled beta-M S H. An arrow points down from the very small purplish blue segment of beta-endorphin to a similar very small purplish blue segment labeled Met-enkephalin.

Some Hormones Are Released by a “Top-Down” Hierarchy of Neuronal and Hormonal Signals

The changing levels of specific hormones regulate specific cellular processes, but what regulates the regulators — what sets the level of each hormone? The brief answer is that the central nervous system receives input from many internal and external sensors — signals about danger, hunger, dietary intake, blood composition, for example — and orchestrates the production of appropriate hormonal signals by the endocrine tissues. For a more complete answer, consider the path of cortisol release by the adrenal gland, triggered by a stress detected by the central nervous system. Figure 23-6 illustrates the “chain of command” in this top-down hormonal signaling hierarchy. The hypothalamus, a pea-size region of the brain (Fig. 23-7), is the coordination center of the endocrine system; it receives and integrates messages from the central nervous system. In response, the hypothalamus produces releasing factors, including corticotropin-releasing hormone (CRH), that pass directly to the nearby pituitary gland through blood vessels and neurons that connect the two glands. The pituitary gland secretes adrenocorticotropic hormone (also called corticotropin or ACTH), which travels through the blood to the adrenal cortex and triggers the release of cortisol. Cortisol, the ultimate hormone in this cascade, acts through its receptor in many types of target cells to alter their metabolism. In hepatocytes, one effect of cortisol is to increase the rate of gluconeogenesis.

A figure shows the cascade of top-down hormone release following central nervous system input to the hypothalamus, including the effects of regulation on some steps. — FIGURE 23-6 Cascade of top-down hormone release following central nervous system input to the hypothalamus. Solid black arrows indicate hormone production and release; broken black arrows indicate the action of hormones on target tissues. In each endocrine tissue along the pathway, a stimulus from the level above is received, amplified, and transduced into release of the next hormone in the cascade. The cascade is sensitive to regulation at several levels through feedback inhibition (thin, dashed arrows) by the ultimate hormone (in this case, cortisol). The product therefore regulates its own production, as in feedback inhibition of biosynthetic pathways within a single cell.

A yellow box labeled central nervous system is indicated by five arrows. Clockwise from the left side, these are labeled pain, fear, infection, hemorrhage, and hypoglycemia. A dashed arrow points down to a green triangle enclosed in a green circle above a yellow box labeled hypothalamus. An arrow points down from hypothalamus to corticotropin-releasing hormone (C R H) (n g), from which a dashed line points down to a green triangle enclosed in a green circle above a yellow box labeled anterior pituitary. An arrow points down from anterior pituitary to corticotropin (A C T H) (micrograms), from which a dashed arrow points down to a green triangle in a green circle above a red box labeled adrenal gland. An arrow points down from adrenal gland to cortisol (m g). A dashed arrow from cortisol points left and then up before branching off to indicate red “X” symbols in red circles next to anterior pituitary and hypothalamus. Three dashed arrows point down from cortisol. From left to right, these dashed arrows point from cortisol to red boxes labeled muscle, liver, and adipose.

A figure shows the neuroendocrine origins of hormone signals by showing the details of the hypothalamus-pituitary system. — FIGURE 23-7 Neuroendocrine origins of hormone signals. Location of the hypothalamus and pituitary gland and details of the hypothalamus-pituitary system. Signals from connecting neurons stimulate the hypothalamus to secrete releasing factors into a blood vessel that carries the hormones directly to a capillary network in the anterior pituitary. In response to each releasing factor, the anterior pituitary releases the appropriate hormone into the general circulation. Posterior pituitary hormones are synthesized in neurons arising in the hypothalamus; the hormones are transported along axons to nerve endings in the posterior pituitary and stored there until released into the blood in response to a neuronal signal.

A head is shown on the left facing to the right with the brain highlighted. A pale roughly horizontal band, the corpus callosum, is shown in the center of the brain. The cerebellum is shown as a roughly spherical structure with irregular edges at the lower left side of the brain to the left of the region where the hindbrain narrows to meet the spinal cord. To the right of the cerebellum and other portions of the hindbrain, a small roughly oval piece hangs down from the horizontal base of the upper part of the brain. This piece is purple on the left and yellow on the right. An arrow points right to show an enlarged version. The left side is labeled posterior pituitary and contains purple vertical strands that end at a small mesh of blood vessels that run horizontally across the bottom. Arrows point from the bases of these purple strands, where there are many small purple dots, into the bloodstream. Text reads, release of posterior pituitary hormones (vasopressin, oxytocin). The large blood vessel entering from the upper left is labeled arteries. A similar vessel exiting from the lower right of the posterior pituitary and a vessel exiting from the bottom of the right half, labeled anterior pituitary, is labeled, veins carry hormones to systemic blood. A mesh of several blood vessels in the anterior pituitary is labeled, capillary network. The background tissue is yellow and purple strands are visible to the right, with small purple dots near the capillaries. Arrows point into the capillaries and accompanying text reads, release of anterior pituitary hormones (tropins). The capillary network of the anterior pituitary extends up alongside purple strands from the posterior pituitary through a narrow stalk to a wider gray area above. The mesh of blood vessels bends horizontally to the left and exits at an artery, Purple neurons are shown above with nuclei and protrusions around their sides and top in the region above the blood vessels, which is labeled hypothalamus. The long purple strands extending down from the neurons are labeled nerve axons. Some end above the blood vessels, where many small purple dots are visible. Others continue across the blood vessels through the stalk to the posterior pituitary below. Arrows show that the purple dots enter the blood vessels. Text reads, release of hypothalamic factors into arterial blood. Additional gray structures are shown around the hypothalamus.

Hormonal cascades such as those responsible for the release of cortisol result in large amplifications of the initial signal and allow exquisite fine-tuning of the output of the ultimate hormone (Fig. 23-6). At each level in the cascade, a small signal elicits a larger response. For example, the initial electrical signal to the hypothalamus results in the release of a few nanograms of corticotropin-releasing hormone, which elicits the release of a few micrograms of corticotropin. Corticotropin acts on the adrenal cortex to cause the release of milligrams of cortisol, for an overall amplification of at least a millionfold.

At each level of a hormonal cascade, feedback inhibition of earlier steps in the cascade is possible; an unnecessarily elevated level of the ultimate hormone or of an intermediate hormone inhibits the release of earlier hormones in the cascade. These feedback mechanisms accomplish the same end as those that limit the output of a biosynthetic pathway (compare Fig. 23-6 with Fig. 22-37): a product is synthesized (or released) only until the necessary concentration is reached. In the blood-clotting cascade (Fig. 6-44) we saw a similar pattern: a signal stimulates a cascade of protein activations; feedback mechanisms limit their action and the duration of the response.

“Bottom-Up” Hormonal Systems Send Signals Back to the Brain and to Other Tissues

In addition to the top-down hierarchy of hormonal signaling shown in Figure 23-6, some hormones are produced in the digestive tract, muscle, and adipose tissue and communicate the current metabolic state to the hypothalamus (Fig. 23-8). These signals are integrated in the hypothalamus, and an appropriate neuronal or hormonal response is elicited.

A figure shows how two-way information flow between tissues and the hypothalamus regulate feeding behavior. — FIGURE 23-8 Regulation of feeding behavior by two-way information flow between tissues and the hypothalamus. When food intake and energy production are adequate, peptide hormones released by the stomach, intestine, and adipose tissue feed back on the hypothalamus to signal satiety and reduce feeding behavior. Other tissue-specific peptide hormones signal inadequate supplies of stored triacylglycerols or low blood glucose levels. All of these signals impinge, directly or indirectly, on AMP-activated protein kinase (AMPK) in the hypothalamus, which integrates these signals and influences feeding behavior and energy-yielding metabolism in the tissues. Nerves carry electrical signals from the brain to the other tissues to complete the information circuit and achieve homeostasis (not shown). TRH, thyrotropin-releasing hormone; GLP-1, glucagon-like peptide-1; GIP, gastric inhibitory polypeptide.

A yellow box at the top of the figure is labeled hypothalamus and contains a gray box labeled A M P K. A dashed arrow points upward to a green triangle enclosed in a green circle and labeled feeding. An arrow labeled T R H points down from hypothalamus to a yellow box labeled pituitary, from which an arrow labeled T S H points down t o a yellow box labeled thyroid. An arrow points from thyroid to the right and then up to thyroxine, from which a dashed arrow points left to a red “X” in a red circle next to hypothalamus. Beneath thyroid, a yellow box labeled beta cells above a yellow box labeled alpha cells are joined and are both labeled pancreas. An arrow points right from beta cells beneath text reading upward-pointing arrow symbol glucose to insulin, from which an arrow points up and the left to the word insulin again, from which a dashed arrow points left to a red “X” in a red circle next to hypothalamus. An arrow points right from alpha cells beneath text reading downward-pointing arrow symbol glucose to the word glucagon. Beneath the two boxes labeled pancreas, a red box is labeled intestine. An upper arrow points left from intestine beneath text reading upward-pointing arrow symbol food to G I P, from which a dashed arrow points to a red “X” in a red circle next to alpha cells. A lower arrow points left from intestine beneath text reading upward-pointing arrow symbol food to G L P – 1, from which a dashed arrow points to a green triangle in a green circle next to beta cells. Beneath intestine, a red box labeled stomach has an arrow pointing left to ghrelin, from which an arrow points up to the word ghrelin again with a dashed arrow pointing right to a green circle enclosed in a green circle next to hypothalamus. A red box labeled adipose tissue has an arrow pointing left beneath text reading downward-pointing arrow symbol fat to adiponectin, from which an arrow points up to the word adiponectin again next to a dashed arrow pointing right to a green triangle enclosed in a green circle next to hypothalamus. Above this, downward-pointing arrow symbol next to glucose is shown with a dashed arrow pointing to a green triangle enclosed in a green circle next to hypothalamus. A second arrow points from the red box labeled adipose tissue. This arrow points right from adipose tissue beneath text reading upward-pointing arrow symbol fat to the word leptin, from which an arrow points up to the word leptin again next to a dashed arrow pointing to a red “X” in a red circle next to the box labeled hypothalamus.

Adipokines, for example, are peptide hormones, produced in adipose tissue, that signal the adequacy of fat reserves. The adipokine leptin, released when adipose tissue is well-filled with triacylglycerols, acts in the brain to inhibit feeding behavior, whereas adiponectin signals depletion of fat reserves and stimulates feeding. Other tissues produce and release other hormones. Ghrelin is produced in the gastrointestinal tract when the stomach is empty and acts in the hypothalamus to stimulate feeding behavior; when the stomach fills, ghrelin release ceases. Incretins are peptide hormones produced in the gut after ingestion of a meal; they increase secretion of insulin and decrease secretion of glucagon from the pancreas. Neuropeptide Y (NPY) is a hormone produced in the hypothalamus and in the adrenal glands. Its release promotes feeding and reduces energy expenditure for nonessential activities. Peptide YY $({PYY}_{3 – 36})$ $bold left-parenthesis bold PYY Subscript bold 3 bold en-dash bold 36 Baseline bold right-parenthesis$ , produced in the intestine, signals satiety in the brain. Irisin is a peptide hormone produced in muscle as a result of exercise; it acts to convert white adipose tissue into beige adipose tissue, which dissipates energy as heat (see Section 23.2).

We return to these hormones (summarized in Table 23-2) when we discuss the regulation of body mass in humans (Section 23.4).

TABLE 23-2 Some Peptide Hormones That Act on Feeding Behavior and Fuel Selection in Mammals
Hormone	Production site(s)	Target tissue(s)	Action(s)
Insulin	Pancreatic β cells	Muscle, adipose, liver	Stimulates glucose uptake and synthesis of glycogen and fat
Glucagon	Pancreatic α cells	Liver, adipose	Stimulates gluconeogenesis and glucose release to blood
Leptin	Adipose tissue	Hypothalamus	Reduces hunger
Adiponectin	Adipose tissue	Muscle, liver, others	Stimulates catabolism and feeding behavior
Ghrelin	Stomach, intestine	Brain	Signals hunger
Incretins: GLP-1, GIP	Intestine	Pancreas	Stimulate insulin release
NPY	Hypothalamus, adrenals	Brain, autonomic nervous system	Stimulates feeding behavior
${PYY}_{3 - 36}$ $PYY Subscript 3 en-dash 36$	Intestine	Brain	Signals satiety
Irisin	Muscle (after exercise)	Adipose	Turns white adipose tissue to beige

SUMMARY 23.1 Hormone Structure and Action

Hormones connect all of the organs in the body, carrying information and signals between the central nervous system and all of the tissues.
Hormones are chemically diverse with a wide range of biological roles. Peptide hormones are synthesized as proteins on ribosomes, then cleaved proteolytically to form the active peptide(s).
Hormones are regulated by a top-down hierarchy of interactions between the brain and endocrine glands: nerve impulses stimulate the hypothalamus to send specific hormones to the pituitary gland, thus stimulating (or inhibiting) the release of a second rank of hormones. The anterior pituitary hormones in turn stimulate other endocrine glands (adrenals, for example) to secrete their characteristic hormones, which in turn stimulate specific target tissues.
Some hormones act in bottom-up signaling: adipose tissue, muscle, and the gastrointestinal tract release peptide hormones that act on other tissues or in the central nervous system.