Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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0026 The hypothalamus is the main regulator of

sympathetic nervous system function. Impulses

from the posterior and lateral hypothalamus result

in generalized discharge of the sympathetic nervous

system, including the adrenal medulla, although

they can also be activated separately. The sym-

pathoadrenal system is characterized by speed and

integration, in that catechol-mediated events can

take place within seconds, and can coordinate vascu-

lar, metabolic, and hormonal components. As dis-

cussed above, these responses occur to a variety of

noxious, threatening, or stressful stimuli. In addition,

the sympathetic nervous system is instrumental in

maintaining an appropriate circulating volume and

cardiac output during changes of posture from supine

to upright. These feedback systems are mediated by

sensors in the carotid sinuses, aorta, and medulla,

which detect changes in circulatory volume and blood

pressure. Although of different embryological origins,

and operating via different regulatory mechanisms,

the hypothalamic–pituitary–adrenocortical system

and the sympathoadrenal system complement each

other in the maintenance of homeostasis and a

stable metabolic milieu in response to many forms of

stress.

See also: Amino Acids: Metabolism; Fatty Acids:

Metabolism; Renal Function and Disorders: Kidney:

Structure and Function; Stress and Nutrition

Further Reading

Baxter J and Tyrrell J (1987) The adrenal cortex. In: Felig P

(ed.) Endocrinology and Metabolism. New York:

McGraw-Hill.

DeQuattro V, Myers M and Campese V (1989) Anatomy

and biochemistry of the sympathetic nervous system.

In: DeGroot L (ed.) Endocrinology. Philadelphia: WB

Saunders.

Ganong W (1991) Review of Medical Physiology. The

Adrenals. Norwalk, CT: Appleton & Lange.

Guyton A (1986) The adrenocortical hormones. In:

Textbook of Medical Physiology. Philadelphia: WB

Saunders.

NHCH

Epinephrine

COMT

Norepinephrine

Dihydroxymandelic

acid

Dihydroxyphenyl

acetic acid

3-Methoxytyramine

Homovanillic

acid

NHCH

Metanephrine

Normetanephrine

3-Methoxy-4-hydroxy

mandelic acid

Dopamine

MAO

COMT

MAO

COMT

fig0010 Figure 10 Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Reproduced

from Goldfien A (1986) The adrenal medulla. In: Greenspan F and Forsham P (eds) Basic and Clinical Endocrinology. Los Altos, CA:

Lange Medical Publications, with permission.

HORMONES/Adrenal Hormones 3139

Hale A and Rees L (1989) ACTH and related peptides.

In: DeGroot (ed.) Endocrinology. Philadelphia: WB

Saunders.

Loriaux DL (1990) The adrenal glands. In: Becker K (ed.)

Principles and Practice of Endocrinology and Metabol-

ism. Philadelphia: JB Lippincott.

Orth D and Kovacs W (1998) The adrenal cortex. In:

Williams Textbook of Endocrinology. Philadelphia:

WB Saunders.

Parker L (1989) Adrenal androgens: normal physiology. In:

Adrenal Androgens in Clinical Medicine. San Diego:

Academic Press.

Thyroid Hormones

J Vanderpas, Faculte

decine, FUNDP, Namur,

Belgium

Iodinated Thyroid Hormones

Thyroid Follicles and their Development

0001 The thyroid gland displays a peculiar, highly organ-

ized architecture characterized by the presence of

spheroidal structures – follicles – that are composed

of a single layer of epithelial cells (thyroid follicular

cells) surrounding a closed cavity (follicular lumen)

filled with colloid, a concentrated solution of thyro-

globulin (Tg). The follicle has been defined as the

morphologic and functional unit of the thyroid.

Notably, during intrauterine life, the onset of thyroid

function (around 10 weeks in humans) coincides with

the appearance of differentiated follicles. It is the

follicular organization, together with the polarity of

the follicular cells, that allows the several biochemical

steps required for thyroid hormone biosynthesis: (1)

secretion of a peculiar protein with iodinated amino

acids in the follicular lumen as exocrine cells; (2)

reabsorption of this peculiar protein, with hydrolysis

of its iodinated amino acids; (3) release of iodo-

thyronines into blood by endocrine secretion.

0002 The follicle cell divides the follicular lumen (where

hormone synthesis begins) and the blood stream,

from where iodine has to be uploaded and where

hormones will be released at the end of the process.

0003 The surface of a polarized thyroid follicular cell is

divided into two functionally distinct, but physically

contiguous regions: an apical and a basolateral

domain. Junctional complexes between cells separate

these two domains and prevent the mixing of

asymmetrically distributed proteins (Figure 1). The

apical domain displays a differentiated tissue-specific

organization characterized by the presence of apical

microvilli and pseudopods, and by the localization of

thyroperoxidase (TPO). Na



symporter (NIS),

epidermal growth factor, and thyroid-stimulating

hormone (TSH) receptors are located in the basal

domain. Thyroid hormone synthesis requires basal-

to-apical transport of iodide and Tg. Conversely, hor-

mone secretion is based on apical-to-basal transport

of Tg and hormones; in addition, a bidirectional ion

transport system controls follicular size.

0004The thyroid primordium of the human embryo is

first visible at 20 embryonic days, as a midline

enodermal thickening in the floor of the primitive

pharynx. It migrates caudally to form a transient

thyroglossal duct, and reaches its final position at

35 embryonic days. Tg is detectable at 60 embryonic

days, and this step corresponds to the occurrence of

fetal thyroid hormone biosynthesis. The early stages

of folliculogenesis are independent of thyrotropin. At

midgestation (18–20 weeks), the hypothalamopitui-

tary–thyroid axis begins to develop, and thyrotropin

is absolutely necessary for thyroid growth and

function.

Biosynthesis of Thyroid Hormones

0005Figure 2 summarizes the process of thyroid hormone

synthesis, which includes active concentration of

TSH-R NIS

TTF-1

TTF-2

Pax8

TPO

NADPH

Oxidase

fig0001Figure 1 Schematic structural representation of thyroid follicu-

lar cell with its polarized architecture. TSH-R, thyroid-stimulating

hormone receptor; NIS, Na/I symporter; Tg, thyroglobulin; TPO,

thyroperoxidase; NADPH, reduced form of nicotinamide adenine

dinucleotide phosphate; TTF-1.

3140 HORMONES/Thyroid Hormones

iodine, incorporation of iodine in thyroglobulin, and

breaking down thyroglobulin to release tetraiodo-

thyronine (T

) and triiodothyronine (T

0006 NIS An active transport mechanism allows thyroid

cells to concentrate iodide (I



) some 20- to 40-fold its

level in extracellular space. This transport system is

sensitive to other inhibiting anions (thiocyanate, per-

chlorate). It is found in other tissues (salivary glands,

mammary gland). In the thyroid, it is restriced to the

basolateral cell membrane. The key protein in the

transport mechanism is the human Na/I symporter

(hNIS). Its synthesis is stimulated by TSH. It is a

12-loop protein, of 65 kDa. It has homology with

the Na/glucose transporter.

0007 hTg Human Tg (hTg) is a 660-kDa protein. It con-

tains 66 tyrosils, and half of them – in maximal

conditions – are able to incorporate iodine in a cova-

lent binding, resulting in mono- or diiodotyrosine

(MIT, DIT) residues. Some iodothyrosine residues

fuse, to form T

with its four iodine atoms and T

with its three iodine atoms. In normal physiological

conditions, Tg contains five residues each of MIT and

DIT, 2.5 of T

and 0.7 of T

. These proportions

depend on iodine supply, and on Tg accumulation in

follicles. Its synthesis and release of thyroid hormones

is under thyrotropin control. Iodine by itself,

independently of thyrotropin, has an autoregulatory

function on Tg synthesis and metabolism.

0008 hTPO Human hTPO is a 103-kDa protein localized

in the apical membrane of the follicular cell. It con-

tains heme and, in the presence of hydrogen peroxide,

it iodinates tyrosil residues of hTg present in the

lumen of the follicles. The iodination process of pro-

teins is not specific to thyroid cells: macrophages

and leukocytes iodinate bacteria proteins through a

similar process, involving myeloperoxidase in place

of hTPO. However, the further step of coupling and

thyroid hormone synthesis is quite specific to the

thyroid. The same hTPO enzyme is responsible for

the coupling of DIT and MIT in T

and T

.Itis

proposed that the loops of hTg polypeptide make

some DIT and MIT residues close, and the TPO

enzyme and hydrogen peroxide interact to produce

free radicals which form a diphenyl ether across the

free radicals.

0009hThOX Reduced nicotinamide adenine dinucleo-

tide phosphate (NADPH) oxidase is essential to pro-

duce hydrogen peroxide at the apical membrane of

the follicular cells. It has recently been identified as a

specific thyroid oxidase, with NADPH and calcium

as substrates. It has a cytochrome moiety.

0010The sites of tyrosine iodination, as well as the sites

of iodotyrosine coupling on Tg molecule are not sto-

chastic, but are hierarchically defined. The number

of iodinated tyrosine residues depends closely on

the iodine supply and on thyrotropin stimulation.

Figure 3 depicts the general scheme of preferential

sites of iodination and coupling. The thyroid stores

its hormones as colloid in the follicular lumen, still

part of the Tg peptide structure. This process guaran-

tees a stable storage of both iodine and iodinated

thyroid hormones in variable-iodine-supply condi-

tions. A normal human adult thyroid accumulates

10–20 mg iodine, which represents a storage for at

least 3 months (required daily administration of

iodine: + 100 mg). This storage depot allows the thy-

roid to dole out thyroid hormones as the body needs

it, and to mobilize it rapidly when called for. Such

Hydrogen peroxide production

Oxidation of iodide in iodine or in iodide free radical (still debated)

Organification of specific tyrosil residues in thyroglobulin

Coupling of iodotyrosines in thyroid hormones

1. NADPH + O

+ Ca

+ NADP

ThOX (thyroid-specific NADPH oxidase)

2. H

+ I

−

TPO

3. I

+ [Tg]−Tyr [Tg]−DIT and [Tg]−MIT

TPO

4. [Tg]−DIT + [Tg]−MIT [Tg]−T

+ [Tg]−T

TPO

fig0002 Figure 2 Oxidation of iodide and iodination of thyroglobulin

(Tg) to produce thyroxine. DIT, diiodotyrosine; NADP(H), (re-

duced) and oxidized nicotinamide adenine dinucleotide phos-

phate; TPO, thyroperoxidase; ThOX, thyroid-specific NADP(H)

oxidase; MIT, monoiodotyrosine.

COOH

2746

2677

26572643

2597

2567

2553

2490

2487

2468

2452

2389

1835

1290

1447

766

795

847 972

532551685

86 124

130 239

2164

fig0003Figure 3 General linear picture of human thyroglobulin poly-

peptide chain. Numbers refer to cDNA sequence. A, B, D, sites of

thyroxine formation; D, site of triiodothyronine formation. Cleav-

age sites of various cathepsins are symbolized by arrows.

Reproduced from Dunn JT (2001) Biosynthesis and secretion

of thyroid hormones. In: DeGroot LJ and Jameson JL (eds) Endo-

crinology WB Saunders, with permission.

HORMONES/Thyroid Hormones 3141

mobilization is accomplished by bringing stored Tg

back from the follicular lumen into the cell, passing it

through endosomal and lysosomal digestive systems,

and delivering free hormone to the basal membrane

for secretion into the circulation. About 70% of Tg’s

iodine is in the form of the inactive precursors MIT

and DIT, which the thyrocyte deiodinates and then

recycles the iodine. The most important enzymes

for Tg degradation are the lysosomal proteases. The

best characterized are the aspartic endopeptidase

cathepsin D and the cysteine endopeptidases cathe-

psin B and L. Peptides produced by the individual

enzymes purified from human thyroids were isolated

and the sites of cleavage identified by analogy to the

cDNA sequence of hTg. Figure 3 summarizes, also,

the major cleavage sites for each enzyme. Cathepsin L

(dotted broken arrows in Figure 3) attacked near

hydrophobic residues, particularly leucine, and its

major cleavage sites were within the C-terminal 400

residues of Tg. Cathepsin D (solid arrow in Figure 3)

preferentially cleaved peptide bonds between hydro-

phobic residues, particularly aromatic ones, similar to

its activity in other tissues. Cathepsin B (dashed

broken arrows) had its principal cleavage sites in

both the N-terminal and C-terminal regions. The

presence of major hormonogenic sites at Tg’s extreme

N- and C-termini may favor selective release of thy-

roid hormone during proteolysis. The endopeptidases

cleave Tg into large peptides that must then be further

degraded by exopeptidases. The several exopepti-

dases identified in the thyroid include dipeptidyl-

peptidases I and II, lysosomal dipeptidase I, and the

carbaxyl exopeptidase N-acetyl-l-pbenolalanyl-l-

tyrosine hydrolase. Also, cathepsin B has exopeptidase

activity, in addition to its role as an endopeptidase.

The combination of cathepsin B and lysosomal

dipeptidase I is sufficient to release T

from its most

important site at residue 5.

0011 The thyroid stimulated by TSH shows prompt and

vigorous engulfment of material from the lumen to

form colloid droplets, which are then internalized

into the thyrocyte and passed through its lysosomal-

degradative pathway. However, under more usual

physiologic conditions, colloid resorption takes place

by micropinocytosis, and endocytotic vesicles are

formed and pass successively through an endosomal

compartment and then into lysosomes. The initial

event in micropinocytosis appears to involve the

entrance of Tg into coated pits, probably without

the intervention of receptors; the amount processed

depends on the availability of endocytotic vesicles

and the amount of Tg in the lumen.

0012 Tg’s structure, specifically, the completion of its

carbohydrate side chains, is important for its traffick-

ing at the apical membrane. Immature Tg molecules

are deficient in both iodine and glycosylation, so they

have exposed N-acetylglucosamine residues. These

residues are recognized by membrane receptors that

apparently direct these immature molecules back to

the Golgi for glycosylation and subsequent iodin-

ation. These observations suggest that Tg molecules

are sorted in the endosomes, perhaps by iodine con-

tent, with immature molecules being recycled and

mature ones readied for degradation and hormone

release.

0013Some proteolytic processing may take place in

endosomes before Tg enters lysosomes. Lysosomal

enzymes are also present in endosomes, where the

acidic pH would favor their activity. Some proteolytic

processing may occur even before endocytosis. For

example, cathepsin B activity has been detected at

the cell surface of cultured thyrocytes. In the same

experimental model, activation of cysteine proteases

permitted T

release at extralysosomal sites, as well as

in the lysosomes, although T

release appeared to be

restricted to lysosomes.

0014Specific cleavages in the peptide chain of Tg are

also associated with its iodination. Such breaks

occurred in the presence of protease inhibitors, thus

suggesting that proteolytic enzymes were not in-

volved. However, other specific proteolytic cleavages

may also occur as early events in Tg degradation.

Limited digestion with trypsin has identified several

susceptible regions in the Tg molecule, most notably a

region after residue 500 and another one around

residue 1800.

0015T

emerges from the lysosomal-degradative path-

way, probably as the free hormone or perhaps in

small peptides. Most is secreted into the circulation.

A specific transport mechanism across the basal

membrane has not been identified. While still in

the thyroid, some T

is converted to T

by type 1

selenium-dependent 5

-iodothyronine deiodinase.

This enzyme is the same as that in other tissues,

such as the liver and kidney, produces T

, the active

form of the hormone, from circulating T

0016About 70% of Tg’s iodine is in MIT and DIT.

Although small amounts of MIT and DITare secreted

into the circulation, most is deiodinated within the

thyroid and its iodide is returned to the general pool

for recycling. This mechanism is important for iodine

conservation, as shown by the functional iodine defi-

ciency of patients who have the rare defect that blocks

this step. The iodotyrosine deiodinase responsible for

this activity is an NADPH-dependent flavoprotein (it

is not a selenium-containing enzyme, and it should

not be confound with iodothyronine deiodinase). Its

partial purification showed a molecular weight of

about 42 000, and it consisted of two possibly

identical subunits.

3142 HORMONES/Thyroid Hormones

Circulating Thyroid Hormone and Free Thyroid

Hormone Metabolism

0017 Iodothyronines produced by the thyroid are highly

hydrophobic, and need to be bound to specific

proteins for transport through the general blood cir-

culation to their target tissues. In blood, thyroid hor-

mones are not covalently bound to specific thyroid

hormone-binding proteins (thyroid hormone-binding

globulin (TBG) and transthyretin (TTR), previously

known as prealbumin). They are also transported

aspecifically by albumin. Table 1 shows the proper-

ties of the major human thyroid hormone-binding

proteins.

0018 Free fraction of thyroid hormones describes the

percentage of total hormone that is unbound. About

one molecule of T

in 4000 and one molecule of T

in 400 is free; the remaining molecules are bound to

the specific and aspecific proteins. By contrast to

corticoid-binding proteins, none of the thyroid

hormone-binding proteins has a role in the delivery

of thyroid hormones to target tissues. Only free hor-

mones are delivered to target tissues: so, clinical thy-

roid status is closely dependent on free thyroid

hormone concentration, and the general equilibrium

is as follows:

Free T

þ TBG ,½TBG ...T



0019 The normal free T

concentration and TBG con-

centration are such that about half of TBG sites avail-

able to thyroid hormone binding is occupied by T

This involves that within a certain range; free hor-

mone concentration is linearly associated with total

hormone concentration. So, TBG stabilizes the tissue

distribution of T

0020 Modern immunoassays measure the serum free T

and free T

concentrations, which are directly related

to clinical thyroid status.

0021 Table 2 presents the kinetic parameters of circulat-

ing total and free thyroid hormones in a 70-kg adult

human.

0022Within some tissues (mainly, liver and kidney),

circulating T

is deiodinated in circulating T

by a

selenium-dependent type 1 iodothyronine deiodi-

nase. In normal iodine supply conditions, half of

circulating T

derives directly from thyroid (break-

down of Tg), and half from liver conversion of T

. The same deiodinase is also able to convert T

to reverse T

(metabolically inactive). In some

physiological conditions such as the neonatal period

(cord blood) or during illness, the preferential liver

conversion of T

to reverse T

explains the paradox-

ical serum profile of low T

syndrome without

hypothyroidism. The exact mechanism of preferen-

tial conversion of T

to reverse T

in place of T

still unexplained.

Thyroid Hormone Action at the Cellular Level

0023Free thyroid hormones T

and T

diffuse through the

cell membrane of their target tissues. Up to now, no

specific membrane receptors have been identified,

and it is considered that this delivery to cells is

through a passive diffusion mechanism.

0024Within the cell, iodothyronine deiodinases act to

convert intracellular T

to intracellular T

or reverse

(Figure 4).

0025The differential intracellular conversion of T

to T

in peripheral tissues (thyroid; muscle, including the

heart; liver; kidney; adipose tissue, etc.) and in central

tissues (central nervous system, including pituitary

gland) is explained by the divergent distribution of

selenium-containing iodothyronine deiodinases. Type

1 is present mainly in peripheral tissues, while type 2

is present mainly in the central nervous system. Type

2 deiodinase has a much lower affinity constant for

than type 1 deiodinase (1 nmol l

1

versus 23 mmol

1

). This explains why, within the central nervous

system, in normal physiological conditions, 80% of

tbl0002Table 2 Kinetic properties of iodothyronines in humans

Property T

ReverseT

Total serum concentration

(mgdl

1

)

8.1 0.11 0.012

Free serum concentration

(ng dl

1

)

1.2 0.29 0.04

Distribution volume (l) 10 35 90

Metabolic clearance rate

(per day 70 kg s

1

)

1.2 25 111

Serum half-life (days) 7 1 0.2

Production

(mg day

1

70 kg s

1

)

100 31 39

Relative metabolic potency 0.3 1.0 0.0

Nuclear T

receptor

binding in vitro

9

10

No data

, tetraiodothyronine; T

, triiodothyronine.

tbl0001 Table 1 Properties of the major human thyroid hormone-

binding proteins

Property Thyroxine-

binding

globulin

Tr a n s t h y r e t i n A lb u m i n

Molecular weight (kDa) 54 55 66

Peptide structure Glycoprotein Peptide

tetramer

Single

chain

Concentration (mol l

1

)310

7

2 10

6

6 10

4

Half-life (days) 5 2 15

% of tetraiodothyronine

carried

75 10–15 10–15

HORMONES/Thyroid Hormones 3143

intracellular T

derives from local deiodination of

, while, in peripheral tissues, this percentage is less

than 50%. Moreover, in case of incipient biochem-

ical hypothyroidism, when serum T

is already de-

creased but serum T

is still normal, there is

increased type 2 deiodinase activity and increased

thyroid type 1 deiodinase activity, while there is

decreased type 1 deiodinase activity in other periph-

eral tissues (liver, mucle, heart, kidney). These mech-

anisms involve central hypothyroidism reflected by

increased serum TSH, while peripheral tissues are

still euthyroid (there is no evidence of hypothyroid-

ism in peripheral tissues). The advantage of such a

complex feedback mechanism is to stimulate max-

imally the thyroid by TSH in case of incipient bio-

chemical hypothyroidism.

0026 At the nuclear level (Figure 5), thyroid hormone

acts through a T

response element (TRE). Most thy-

roid hormone activity described up to now is medi-

ated via these high-affinity nuclear receptors – even if

some extranuclear actions of thyroid hormones are

also described. The principal differentiation effects of

thyroid hormones (brain development, bone matur-

ation) and the metabolic effects of thyroid hormones

(uncoupling protein, fatty acid metabolism, malic

enzyme activity) are mediated via these receptors.

The binding of thyroid hormone T

to its receptor

involves an induction (positively regulated genes) or a

repression (negatively regulated genes) of specific

messenger RNAs and the translation of these

mRNAs in specific proteins. Examples of positively

regulated genes include b-adrenergic receptor, fatty

acid synthetase, malic enzyme, growth hormone, un-

coupling protein, and type 1 iodothyronine deiodi-

nase (except in thyroid). Examples of negatively

regulated genes are TSH, prolactin, type 2 iodothyr-

onine deiodinase, and type 1 iodothyronine deiodi-

nase in thyroid.

0027The translated protein may also act indirectly, for

example, thyroid hormones influence growth via

insulin-like growth factor 1 (IGF-1). Nevertheless,

this action is not present in hypophysectomized rats.

So, the thyroid hormone action on liver IGF-1 is

indirect:

*!Pituitary and circulating growth hormone *

! Liver and circulating IGF-1 *

0028The TRE belongs to the family of erb-related recep-

tors (including receptors for estrogen, progesterone,

glucocorticoid, mineralocorticoid, androgen, vitamin

D, retinoic acid). The receptor binds to the DNA via

zinc-fingers. It forms a dimer which is stabilized when

bound to T

(homodimer) or to 9-cis-retinoic acid

(heterodimer).

0029A congenital mutation in TRE is a – rare – cause of

resistance to thyroid hormones (200 cases have been

Cytoplasm

Circulating T

TRE

Nucleus

Gene

Se-Diase 1

mRNA

fig0005Figure 5 Simplified model of thyroid hormone action on

nuclear thyroid hormone receptor. T

, tetraiiodothyronine; T

triiodothyronine; Se-Diase 1; selenium-dependent iodothyronine

deiodinase 1; TRE, T

response element.

TSH

Pituitary

Thyroid

Liver

Cellular level

TG-T

Circulating T

TG-T

TG-MIT

TG-DIT

Se-Diase 1

Se-Diase 1 or 2

Nuclear T

receptor

−

fig0004 Figure 4 Some metabolic steps in iodine metabolism. Pituitary

thyrotropin (TSH) stimulates thyroid I



uptake, and enzymatic

organification of iodine (I

) by thyroperoxidase (TPO) in a mono-

and diiodotyrosine (MIT and DIT), which are further coupled by

the same enzyme thyroperoxidase (TPO) in tri- and tetraiodo-

thyronine (T

and T

). Part of T

is further deiodinated to T

the liver by selenium-containing enzymes selenium-dependent

iodothyronine deiodinases 1 and 2 (Se-Diase 1 and 2). At the

cellular level, the active hormone is T

, which binds to a specific

nuclear T

receptor. T

comes directly from circulating serum T

or from the intracellular conversion of T

to T

3144 HORMONES/Thyroid Hormones

described in the world) characterized by elevated

serum free T

and elevated serum TSH. Individuals

with this syndrome do not in general exhibit signs of

hypothyroidism, presumably because the resistant

state is compensated for by increased levels of thyroid

hormones. In some cases, the syndrome may include

attention-deficit hyperactivity disorder, reduced intel-

lectual development, delayed skeletal maturation,

tachycardia, and deafness.

Calcitonin

0030 Thyroid also synthesizes calcitonin. The parafollicu-

lar or C cells are distributed among follicular cells.

These cells derive from the neural crest (by opposi-

tion to the endodermal origin of follicular cells). In

human adults, these cells represent less than 1% of

the follicular cells. Parafollicular cells are also secret-

ing other hormones like gastrin and somatostatin.

During ontogeny, around embryonic day 24 in

humans, C cells of neural crest origin colonize a ves-

tigial organ – the ultimobranchal organ, derived from

the fourth pharyngeal pouch. This ultimobranchial

organ, with its embryonic C cells, migrates toward

the thyroid, where its cells diffuse among the folli-

cules.

0031 Calcitonin is derived from a 136 amino acid pre-

cursor peptide which, after cleavage, leaves an active

protein of 32 amino acids.

0032 Calcitonin inhibits bone resorption, peculiarly

during growth. For example, it decreases serum cal-

cium after administration of pharmacologic doses. In

adults, however, the effect of calcitonin on calcium

homeostasis is marginal. Moreover, children born

without thyroid (thyroid aplasia) and adequately

treated with substitutive T

hormonetherapy do not

present alterations of calcium homeostasis nor osteo-

porosis. So, if there is no doubt that calcitonin exerts

an effect at pharmacological doses, its role in normal

human physiology, even during growth, remains

largely unknown.

See also: Iodine: Properties and Determination;

Physiology

Further Reading

Caillou B, Dupuy C, Lacroix L et al. (2001) Expression of

reduced nicotinamide adenine dinucleotide phosphate

oxidase (ThoX, LNOX, Duox) genes and proteins in

human thyroid tissues. Journal of Clinical and Endo-

crinological Metabolism 86: 3351–3358.

Gut Hormones

L M Morgan, University of Surrey, Guildford, UK

Introduction

0001The gut is the body’s largest endocrine organ, both in

terms of the number of endocrine cells and number of

hormones. The very word ‘hormone’ was first used by

Bayliss and Starling in 1902 to describe the action of

the gastrointestinal (GI) hormone secretin. However,

the firm establishment of the gut’s endocrine status

was not achieved until 1970 when the primary struc-

ture of the three classical endocrine gut hormones

secretin, gastrin, and cholecystokinin (CCK) was

finally determined. Since the 1970s there has been a

rapid explosion in our knowledge of the variety and

complexity of bioactive peptides found in the gut,

made possible by new investigative technologies, es-

pecially those of molecular biology. The gut has been

shown to contain not only endocrine hormones but a

huge variety of neuropeptides, and many gut peptides

which were formerly believed to be classical hormones

have since been shown to be widespread neurotrans-

mitters. This has led to a much broader understand-

ing of the diversity of physiological roles for gut

peptides. These roles extend far beyond the absorp-

tion and digestion of food in the gut itself to the

coordination and regulation of many bodily functions

outside the gut. This article reviews the major hor-

mones of the GI tract, their characteristics, physio-

logical effects, and the regulation of their secretion by

nutrients and other stimuli. It focuses on those aspects

of gut hormone physiology that are concerned with

the digestion and metabolism of nutrients and the role

of gut hormones in the regulation of appetite and

food intake itself.

Distribution and Synthesis

0002GI hormones were first identified within gut endo-

crine cells, which are scattered throughout the

mucosal epithelium lining the gastric glands, intes-

tinal crypts, and villi. Typically these cells are pyr-

amidal and lie on the basement membrane. Some

cells extend to the lumen of the gut by means of

tufts of microvilli and some connect to one another

via cytoplasmic processes. In addition, the neuronal

cells of the gut which form the submucosal and

myenteric plexi also produce a wide variety of gut

peptides. The peptide-secreting cells share many fea-

tures, and they were probably derived from a

common precursor cell that differentiated to

HORMONES/Gut Hormones 3145

produce each endocrine or neurocrine cell line, a

hypothesis which accounts for the widespread distri-

bution of gut peptides outside the gut itself, in

neural tissue and the central nervous system. With

the exception of secretin, gastric inhibitory polypep-

tide (GIP), and peptide YY (PYY), most of the gut-

regulatory peptides are indeed also present in brain

tissue. Many of the gut peptides thus act as para-

crine or neurocrine transmitters rather than as endo-

crine hormones. This enables many functions of the

digestive tract, e.g., secretory or motor functions, to

be regulated by interaction between the endocrine

and nervous systems. In addition, gut neuropeptides

are involved in many centrally mediated functions,

such as the perception of appetite and regulation of

food intake.

0003The GI hormones are low-molecular-weight single-

chain polypeptides, of chain length generally fewer

than 50 amino acids. Most are synthesized by a pro-

hormone mechanism in a manner similar to insulin.

However, unlike insulin, GI hormone genes often ex-

press several different bioactive peptides. After the

initial translation productof thegene is formed, a series

of modifications, collectively called posttranslational

processing, can result in a number of peptide products

of varying chain lengths and biological activities.

Characterization

0004The major gut hormones of known structure are

listed in Table 1, together with the primary attributes

by which they have been characterized. Each year

tbl0001 Table 1 Distribution and biological actions of the major gastrointestinal (GI) hormones

Hormone/peptide Site of distributionin GI tract Major biological effects

Secretin family

Secretin Endocrine cells, duodenum, and jejunum Stimulation of pancreatic exocrine secretion

Gastric-inhibitory polypeptide Endocrine cells, duodenum, and jejunum Stimulation of insulin secretion

Glucagon-like peptides (GLP-1, GLP-2,

glicentin, oxyntomodulin)

Endocrine cells throughout GI tract. Highest

concentrations in terminal ileum and

colon

Stimulation of insulin secretion and satiety.

Inhibition of gastric acid secretion. Trophic

effect on gut mucosa

Vasoactive intestinal peptide Nerve fibers throughout GI tract Modulation of gut motility. Stimulation of

intestinal secretion. Regulation of blood

flow

Gastrin family

Gastrin Endocrine cells, antrum, and duodenum Stimulation of gastric acid secretion.

Trophic actions on gut mucosa

Cholecystokinin Endocrine cells, duodenum, and jejunum

Nerve fibers, pancreas, and colon

Stimulation of pancreatic secretion,

gallbladder contraction, satiety. Inhibition

of gastric emptying

Pancreatic polypeptide family

Pancreatic polypeptide Endocrine cells, pancreas Inhibition of pancreatic exocrine, gastric

acid secretion

Peptide YY Endocrine cells throughout GI tract.

Highest concentrations in terminal ileum

and colon

Inhibition of gastric acid secretion, gastric

emptying, intestinal motility

Neuropeptide Y Nerve fibers throughout GI tract. Pancreas Inhibition of intestinal and insulin secretion

Tachykinin family

Substance P Nerve fibers throughout GI tract



Smooth-muscle contraction regulation of

blood flowNeurokinin A (neuromedin L) Nerve fibers throughout GI tract

Neurokinin B (neuromedin K) Nerve fibers throughout GI tract

Bombesin-like peptides

Gastrin-releasing peptide Nerve fibers throughout GI tract

Smooth muscle contraction. Trophic

actions on gut mucosa. Stimulation of

gastrin

Neuromedin B Nerve fibers throughout GI tract

Somatostatin Endocrine cells, nerve fibers throughout GI

tract, especially stomach, colon, pancreas

Inhibition of many gut peptides, especially

gastrin and insulin; gastric, pancreatic,

and biliary secretion

Neurotensin Nerve and endocrine cells throughout GI

tract, especially ileum and jejunum

Inhibition of gastric motility and secretion

Stimulation of pancreatic exocrine secretion

Motilin Endocrine cells throughout small intestine,

especially duodenum, jejunum

Regulation of interdigestive gut motility.

Inhibition of gastric motor activity

Galanin Nerve fibers throughout GI tract, pancreas Inhibition of gastric emptying, gut motility,

insulin, and other gut peptide secretion

3146 HORMONES/Gut Hormones

several new bioactive peptides are added to the grow-

ing list of GI hormones, and currently the number of

regulatory peptides isolated from the GI tract is well

in excess of 50. Many of the GI hormones show a

large degree of structural homology, and can be

divided up into distinct families on the basis of simi-

larities in their amino acid sequence. There is often

considerable overlap in the biological activities of

hormones in the same group, for example most

members of the secretion family have the ability to

potentiate insulin secretion. Gut peptides which do

not fit into family groups are termed ‘orphan’ pep-

tides. The ability of GI hormone genes to express

multiple phenotypes has led to great molecular het-

erogeneity and complexity of their hormone prod-

ucts. For example, secretin was originally believed

only to exist as a 27-amino-acid peptide. However,

by 1990, three additional secretins with full bioactiv-

ity had been identified, two of similar size to secretin-

27 and formed by variable trimming of secretin-27’s

carboxyl terminal, and one large bioactive molecule,

secretin-71, produced by trimming out the mid-

sequence of the prohormone, preprosecretin. Pro-

hormones can also contain more than one active

sequence. Within the secretin family, a group of closely

related glucagon-like peptides is derived from a single

preproglucagon gene. Posttranslational processing is

cell-specific; thus in the pancreas glucagon is the hor-

monal gene product, whilst in the gut, glicentin and

oxyntomodulin (extended versions of glucagon) are

produced, together with two additional bioactive

peptides, glucagon-like peptides 1 and 2.

0005 Some of the neurally distributed gut peptides were

first isolated from brain tissue. Somatostatin was

originally isolated and characterized from the hypo-

thalamus before its discovery in gastric mucosal cells

and the pancreas. The enkephalins, members of the

tachykinin family, were first isolated from brain

tissue, where they are often detectable in higher

concentrations than in tissues within the GI tract.

0006 The gut hormones occurred very early on in evolu-

tionary terms and various members of the gut hor-

mone families are extensively distributed throughout

the animal kingdom. Some of the mammalian gut

hormones have amphibian counterparts. The bombe-

sin-like peptides, of which gastrin-releasing peptide

(GRP) is the chief mammalian example, were origin-

ally isolated in amphibian skin. In addition, neuro-

tensin, CCK and the tachykinin, substance P, have

their amphibian skin counterparts – xenopsin, caeru-

lein, and physalaemin respectively. Substance P and

CCK-like peptides have been found in invertebrate

neurons and a CCK-like peptide has even been isol-

ated in hydra, one of the simplest present-day multi-

cellular organisms.

Physiological Effects

0007Gut peptides can be separated into three functional

categories: endocrine, paracrine, and neurocrine,

reflecting their cellular location and mode of delivery

to target cells (Table 2). Endocrine peptides reach

their targets via the general circulation, paracrine by

diffusion or via the local circulation, and neural pep-

tides by synaptic transmission.

0008Essential first steps in identifying the physiological

function of a gut peptide are to determine its cellular

location, pharmacological properties, and the regula-

tion of its secretion. This is hindered by two features of

the neurendocrine system of the gut. The first

is the wide dispersion and comingling of peptide-

containing cells which make it difficult to excise

one endocrine or neural system without interfering

with another. The second feature, characteristic of

neurons, is the existence of different peptides within

the cell along with nonpeptide neurotransmitters,

leading to the possibilities of very complex inter-

actions. Nevertheless, the physiological roles of gut

hormones in several major functions of the GI tract

and the interaction between endocrine and nervous

systems have been elucidated and are described below.

Control of Gastric, Pancreatic, and Biliary

Secretion

0009There are three major endogenous stimulators of gas-

tric acid secretion: gastrin, acetylcholine, and hista-

mine; it is probable that all three are interdependent

under physiological conditions in humans. The major

action of gastrin is to release acid from parietal cells

in the fundus and body of the stomach, although

it also exerts indirect effects on acid secretion via

the stimulation of histamine release from ECL cells.

Regulation of gastrin secretion is under the control

of both humoral and local factors and also the

tbl0002Table 2 Functional categories of gut hormones

Hormone Endocrine Paracrine Neurocrine

Secretin þ

Gastric-inhibitory peptide þ

Glucagon-like peptides þ

Vascular-inhibitory peptide þ

Gastrin þ

Cholecystokinin þþ

Pancreatic polypeptide family þþ

Tachykinin family þ

Bombesin-like peptides þ

Somatostatin þþþ

Neurotensin þ

Motilin þþ

Galanin þ

HORMONES/Gut Hormones 3147

autonomic nervous system, illustrating the complex

interaction between endocrine, neurocrine, and para-

crine systems. Gastrin release is stimulated directly by

the ingestion of food, especially protein, and by the

neuropeptide GRP, which is itself released by choli-

nergic stimulation. Gastrin secretion is inhibited by

acid, and by somatostatin, acting in a paracrine

manner. The ingestion of fat, once the fat has passed

though the stomach and into the small intestine, in-

hibits gastric acid secretion via the stimulation of GI

hormones GIP, glucagon-like polypeptide-1 (GLP-1),

and CCK. It seems likely that their modes of action

vary and include both direct inhibitory effects on

parietal cells, as in the case of CCK, and indirect

effects on acid secretion via gastrin and somatostatin.

0010 Pancreatic exocrine secretion contains two major

components. The first is an aqueous solution contain-

ing a high concentration of bicarbonate whose

function is to neutralize acid entering the duodenum

from the stomach. The second is a solution of

enzymes which aid the absorption and digestion of

carbohydrate, fat, and protein. Secretin and cholecys-

tokinin are traditionally thought to be responsible for

pancreatic exocrine secretion, but other gut peptides,

notably vasoactive intestinal peptide (VIP), neuroten-

sin, and pancreatic polypeptide, may also influence

secretion. Secretin is responsible for most of the water

and bicarbonate secretion. CCK acts synergistically

with secretin to augment pancreatic bicarbonate

output, and interactions between neurotensin and

secretin also appear to be important. During diges-

tion, pancreatic exocrine secretion is partly controlled

by efferent vagal fibers, mediated by VIP. Pancreatic

polypeptide inhibits pancreatic secretion and may

be involved with the damping-down of pancreatic

exocrine secretion following a meal.

0011 CCK has been considered a major hormone con-

trolling gallbladder emptying, and release of pancre-

atic enzymes. However, the lack of reliable assays

to measure circulating levels of CCK has caused dif-

ficulty in ascribing a physiological, as opposed to

pharmacological, role for the hormone. Recent stud-

ies using CCK-A (the predominant CCK receptor

found in the pancreas and gallbladder) receptor

antagonists have confirmed the role of CCK as

the primary stimulator of gallbladder contraction,

although the effects of CCK receptor antagonists on

pancreatic secretion are less clear, probably reflecting

multiple pathways of control for pancreatic exocrine

secretion.

Gastric Emptying and Gut Motility

0012 Between the striated muscles of the esophagus and the

external anal sphincter, which are dependent upon

efferent nerves for proper functioning, lie the smooth

muscles which form the bulk of the GI tract. They are

capable of executing their function without extrinsic

innervation, and sympathetic and parasympathetic

nerves act only in a modulatory capacity. The intrin-

sic nerves of the gut form two major networks or

plexi: the myenteric plexus which lies between the

longditudinal and circular muscles of the gut, and the

submucous plexus, which lies between the mucosa

and circular muscle layer. Control of gut motility

involves many neuronally located gut peptides. Re-

ceptors for many peptides have been located on gut

smooth muscle cells, including motilin, the opioid

peptides, the tachykinins, VIP, and neuropeptide Y.

0013Regulation of the rate of gastric emptying depends

on many factors, including the physical state and size

of the meal and its macronutrient content. Three

endocrine gut hormones have been implicated in the

control of gastric emptying. Secretion of CCK is

responsible for the delay in gastric emptying when

fat is added to a meal; the presence of fat in the

duodenum is a powerful stimulus for CCK release.

GLP-1, secreted in response to the presence of all

three macronutrients in the upper small intestine,

also delays gastric emptying and regulates the influx

of nutrients into the upper part of the gut. Peptide YY,

which is colocalized and often cosecreted with GLP-

1, inhibits gastric emptying and also small intestinal

motility. It has been termed the ‘ileal brake’ and

its actions following a meal are thought to enable

sufficient time to occur for the meal’s absorption.

Following the ingestion of food, waves of alternate

contraction and relaxation descend from the gut, fa-

cilitating the passage of food and aiding its absorp-

tion. VIP causes smooth muscle relaxation and its

distribution is consistent with the role of a transmitter

in the descending inhibitory nerves. Opioid peptides

increase the contractile activity of the gut and their

net effect is to slow the transit of food. The tachyki-

nins also have potent exitatory and spasmogenic

effects on smooth muscle and appear to be involved

in regulation of the peristaltic reflex.

0014When fasting is prolonged, interdigestive myoelec-

tric complexes occur. These are waves of contraction

beginning in the stomach which move slowly down

the small intestine, whose function is to clear out the

intestine between feeds and keep the intraluminal

bacterial population low. Motilin is primarily in-

volved in the regulation of this interdigestive activity.

Potentiation of Insulin Secretion and other

Metabolic Effects

0015One of the more important metabolic actions of gut

hormones is their ability to modulate insulin secre-

tion. Orally administered glucose leads to far higher

circulating insulin levels than the same amount of

3148 HORMONES/Gut Hormones