1034 Section VIII • The Endocrine System

growth in vitro. This finding led to the hypothesis that, in tating the action of these hormones. The local free fraction
animals, GH provokes the secretion of another circulating of IGF-1 is probably the more biologically active component
factor that “mediates” the action of GH. Initially called “sul- that binds to the receptor and stimulates tissue growth.
fation factor” because of how it was assayed, this intermedi- Like other peptide hormones, IGF-1 and IGF-2 are syn-
ate was subsequently termed somatomedin because it thesized through the secretory pathway (see Chapter 2) and
mediates the somatic effects of GH. The responsible proteins are secreted into the extracellular space, where they may act
were isolated and purified and were found to be identical to locally in a paracrine fashion. In the extracellular space, the
two peptides with a primary structure much like that of IGFs encounter binding proteins that may promote local
proinsulin, and they were termed IGFs (Fig. 48-5). These retention of the secreted hormone by increasing the overall
peptide hormones are made in various tissues, including the molecular size of the complex. This action inhibits the entry
liver, kidney, muscle, cartilage, and bone. They are called of the IGFs into the vascular system. Thus, local concentra-
“insulin-like” growth factors because they exert insulin-like tions of the IGFs are likely to be much higher than plasma
actions in isolated adipocytes and can produce hypoglyce- concentrations.
mia in animals and humans. The liver produces most of the Whether made locally or reaching tissue through the cir-
IGF-1 present in the circulation. IGF-1 production appears culation, IGF-1 acts through a specific receptor tyrosine
to be more closely related to GH secretion than does IGF-2 kinase (see Chapter 3), a heterotetramer that is structurally
production. related to the insulin receptor (Fig. 48-6). Like the insulin
receptor (see Chapter 51), the IGF-1 receptor has two com-
pletely extracellular α chains and two transmembrane β
GROWTH-PROMOTING HORMONES chains. Also like in the insulin receptor, the β chains have
the intrinsic tyrosine kinase activity. Binding of IGF-1 to its
receptor enhances receptor autophosphorylation as well as
Insulin-like growth factor 1, which interacts with
phosphorylation of downstream effectors. The structural
a receptor similar to the insulin receptor, is the
homology between the insulin and IGF-1 receptors is suffi-
principal mediator of the growth-promoting
ciently high that insulin can bind to the IGF-1 receptor,
action of growth hormone
although with an affinity that is approximately two orders
The synthesis of IGF-1 and, to a lesser extent, IGF-2 depends of magnitude less than that for IGF-1. The same is true for
on circulating GH. As described earlier, the periodic nature the binding of IGF-1 to insulin receptors. In fact, the homol-
of GH secretion results in a wide range of plasma GH con- ogy between the insulin and IGF-1 receptors is so strong that
centrations. In contrast, plasma [IGF-1] does not vary by hybrid receptors containing one α-β chain of the insulin
more than ~2-fold over a 24-hour period. The plasma [IGF- receptor and one α-β chain of the IGF-1 receptor are present
1] in effect integrates the pulsatile, highly fluctuating GH in many tissues. These hybrid receptors bind both insulin
concentration. The reason for the relatively steady plasma and IGF-1, but their affinity for IGF-1 is greater.
levels of IGF-1 is that like GH—but unlike most peptide Given the structural similarity between insulin and IGFs
hormones—IGF-1 circulates bound to several IGF-1– and between the insulin receptor and the IGF-1 receptor, it
binding proteins. These binding proteins are made princi- is not surprising that IGFs can exert insulin-like actions in
pally in the liver, but they are also manufactured by other vivo. This effect has been particularly well studied for IGF-1,
tissues. More than 90% of IGF-1 measured in the serum is which, like insulin, induces hypoglycemia when it is injected
bound to these proteins. At least six distinct IGF-binding into animals. This action is largely the result of the increased
proteins have been identified. In addition to providing a uptake of glucose into muscle tissue. IGF-1 is less effective
buffer pool in plasma of bound IGF, these proteins may also in mimicking insulin’s action on adipose and liver tissue; in
aid the transfer of IGF to the tissue receptors, thereby facili- humans, these tissues have few IGF-1 receptors. In muscle,

B C A
Human insulin 30 AA 31 AA 21 AA

Of 29 amino acids in IGF-I,

13 are homologous with 13/29 homology 11/21 homology
insulin B domain.
D
IGF-1 29 AA 12 AA 21 AA

22/29 homology 18/21 homology 4/6 homology

D
IGF-2 29 AA 12 AA 21 AA

Figure 48-5 Structure of the IGFs. Insulin, IGF-1, and IGF-2 share three domains (A, B, and C), which have
in common a high degree of amino acid sequence homology. The C region is cleaved from insulin (as the
C peptide) during processing, but it is not cleaved from either IGF-1 or IGF-2. In addition, IGF-1 and IGF-2
also have a short D domain.
 Chapter 48 • Endocrine Regulation of Growth and Body Mass 1035

Extracellular
IGF-1
space
RECEPTOR
IGF-2
N N MANNOSE-6-
INSULIN PHOSPHATE
RECEPTOR RECEPTOR
α
N N N
S S
S S
S S
α

S S
S S
S S Receptor
domain

β β
C

C C C C

Tyrosine Tyrosine
kinase kinase
domains domains
Cytosol

Figure 48-6 Comparison of insulin, IGF-1, and IGF-2 receptors. Both the insulin and IGF-1 receptors are
heterotetramers joined by disulfide bonds. For both, the cytoplasmic portions of the β subunits have tyrosine
kinase domains as well as autophosphorylation sites. The IGF-2 receptor (also called M6P receptor) is a
single polypeptide chain with no kinase domain.

IGF-1 promotes the uptake of radiolabeled amino acids and 48-6). The IGF-2 receptor lacks a tyrosine kinase domain and
stimulates protein synthesis at concentrations that do not does not undergo autophosphorylation in response to the
stimulate glucose uptake, findings indicating that the growth- binding of either IGF-2 or IGF-1. The IGF-2 receptor also
promoting actions of IGF-1 are expressed at lower cir- binds mannose-6-phosphate (M6P), but at a site different
culating concentrations than those required to produce from that for IGF-2 binding, and the receptor’s physiological
hypoglycemia. role appears to be in processing mannosylated proteins by
targeting them for lysosomal degradation. Thus, the term
IGF-2 receptor is somewhat of a misnomer; the IGF-2 recep-
Insulin-like growth factor 2 has actions similar
tor’s role in the physiological action of IGF-2 is not clear.
to those of insulin-like growth factor 1 but is
Despite these differences, IGF-2 does share with IGF-1
less dependent on growth hormone
(and also with insulin) the ability to promote tissue growth
The physiology of IGF-2 differs from that of IGF-1 in certain and to cause acute hypoglycemia. These properties appear
important respects. First, as noted earlier, the synthesis of to result from IGF-2’s structural similarity to proinsulin and
IGF-2 depends less on circulating GH than does that of IGF- its ability to bind to the IGF-1 receptor.
1. In pituitary dwarfism secondary to GH deficiency, the
circulating concentration of IGF-1 is decreased, but that of
Although growth rate usually parallels plasma
IGF-2 is not. In states of excessive GH secretion, plasma
levels of insulin-like growth factor 1, the two
IGF-1 is reliably elevated, whereas plasma IGF-2 is not.
diverge both early and late in life
Although IGF-2 also binds to the IGF-1 receptor, it pref-
erentially binds to its own so-called IGF-2 receptor. This Illustrated in Figure 48-7 is the mean concentration of total
IGF-2 receptor consists of a single-chain polypeptide and IGF-1 (both free and bound) found in human serum as a
is structurally very distinct from the IGF-1 receptor (Fig. function of age. Also shown is the normal rate of height
1036 Section VIII • The Endocrine System

increase (cm/yr). During puberty, the greatest growth rates Whereas good general concordance exists between growth
are observed at times when plasma [IGF-1] is highest. A rate and the plasma [IGF-1] during puberty, the two diverge
similar comparison can be made using GH, provided care is at both younger and older ages. First, during adulthood,
taken to obtain multiple measurements at each age and longitudinal growth essentially ceases, yet secretion of GH
thereby account for the pulsatile secretion and marked and of IGF-1 continues to be highly regulated. As both men
diurnal changes that occur in plasma [GH]. and women age, the circulating concentrations of both hor-
mones decline. For many years, the continued secretion of
these hormones in adults was considered to be largely vesti-
Plasma Level of IGF-1 as a Measure of gial. This belief was reinforced by the observation that ces-
Growth Hormone Secretion sation of GH secretion and the consequent decline of IGF-1
after trauma, tumor, or surgical removal of the pituitary did
not result in any clear clinical syndrome. However, with the

T
he plasma concentration of IGF-1 is a valuable measure
of GH secretion. The wide swings in plasma [GH] that availability of recombinant human GH, replacement of GH
result from the pulsatile secretion of this hormone in GH-deficient adults has led to remarkable increases in
have confounded efforts to use GH measurements to diag- body muscle mass, decreases in fat mass, and improved
nose disorders of GH deficiency or excess. However, an nitrogen balance (a measure of protein nutrition). These
increased circulating concentration of IGF-1 is one of the findings support the conclusion that—even after linear
most useful clinical measures of the excess GH secretion growth ceases after puberty—GH and IGF-1 remain impor-
that occurs in acromegaly (i.e., GH excess in adults) and tant regulators of body composition and appear to promote
gigantism (i.e., GH excess in children). Measurement of anabolic actions in muscle. Indeed, some investigators have
plasma [IGF-1] has also helped to explain the genesis of a suggested that supplementing physiologically normal adults
particular type of dwarfism known as Laron dwarfism. These with GH or IGF-1 may reverse some of the effects of aging,
patients were initially identified as persons with growth including loss of muscle mass, negative nitrogen balance,
failure mimicking that of typical pituitary dwarfism; however, and osteoporosis.
plasma [GH] is normal or elevated, and treatment with GH A second period of life during which divergence between
is ineffective in reversing the growth failure. It was subse- longitudinal growth and IGF-1 occurs is very early child-
quently demonstrated that these individuals have mutations
hood (Fig. 48-7). This period is characterized by a very rapid
of their GH receptors that make the receptors nonfunctional.
growth rate, but quite low IGF-1 levels. If this time frame is
Thus, the mutant GH receptors cannot trigger the produc-
tion of IGFs. With the availability of recombinant IGF-1, it is
extended back to intrauterine life, then the discordance is
possible that effective treatment of these children will even greater. Indeed, children with complete GH deficiency
restore growth. have very low plasma [IGF-1] levels but are of normal length
Despite the structural similarity of their receptors, IGF-1 and weight at birth. This observation suggests that during
and insulin exert different actions on tissues. IGF-1 has a intrauterine life, factors other than GH and IGF-1 are impor-
more marked effect on growth, and insulin has a more sig- tant regulators of growth. One of these additional factors
nificant effect on glucose and lipid metabolism. However, may be insulin, as discussed later.
the differences in the postreceptor signaling pathways trig- Another explanation for the divergence between growth
gered by the two hormones have not been well defined. rate and IGF-1 levels may be IGF-2, which may be an impor-
tant mediator of intrauterine growth. The plasma concentra-

1000 20

Figure 48-7 Serum IGF-1 levels and

800 The pubertal peak rate of 16 height velocity as a function of age. The
growth corresponds to the peak red curve shows the mean plasma
serum concentrations of IGF-1. concentrations of IGF-1 as a function
Plasma of age in female humans. The curve
600 12 for male humans is similar, but the
[IGF-1] Rate of
(μg/liter) height peak is shifted to an older age by 3 to
increase 4 years. The brown curve indicates
400 8 (cm/yr) mean female height velocity—the rate
IGF-1 in serum at which height increases (cm/yr). The
pubertal peak rate of growth corre-
sponds to the peak serum concentra-
200 4 tions of IGF-1. (Data from Reiter EO,
Rosenfeld RG: Normal and aberrant
growth. In Wilson JD, Foster DW, Kro-
Rate of height increase
nenberg HM, Larsen PR [eds]: Williams
0 0 Textbook of Endocrinology, 9th ed,
0 10 12 20 30 40 pp 1427-1507. Philadelphia: WB
Age Saunders, 1998.)
 Chapter 48 • Endocrine Regulation of Growth and Body Mass 1037

tion of IGF-2 is greater during fetal life than later, and it function at birth, development of hypothyroidism at any
peaks just before birth. Plasma [IGF-2] plummets soon after time before epiphyseal fusion leads to growth retardation or
birth, but then it gradually doubles between birth and age 1 arrest. Much of the loss in height that occurs can be recov-
year and remains at this level until at least the age of 80 years. ered through thyroid hormone treatment, a phenomenon
Thus, IGF-2 levels are at adult levels during the first several called catch-up growth. However, because the diagnosis of
years of life, when IGF-1 levels are low but growth is rapid. hypothyroidism may elude detection for many months or
However, several other hormones may also contribute to years, delays in initiating treatment can lead to some loss of
somatic growth during the first several years of life. potential growth. A child’s growth curve can provide a par-
By age 3 or 4 years, GH and IGF-1 begin to play major ticularly sensitive early indicator of hypothyroidism.
roles in the regulation of growth. The concentrations of
these hormones rise throughout childhood and peak during Sex Steroids As with thyroid hormones, the importance
the time of the pubertal growth spurt. The rate of long bone of sex steroids for growth is most readily understood by
growth in the pubertal growth spurt is exceeded only during considering the effects of deficiency or excess of these hor-
intrauterine life and early childhood. The frequency of pitu- mones. Androgen or estrogen excess occurring before the
itary GH secretory pulses increases markedly at puberty. pubertal growth spurt accelerates bone growth. However,
The factors responsible for this acceleration are not clear. the sex steroids also accelerate the rate at which the skeleton
However, the accompanying sexual maturation likely plays matures and thus shorten the time available for growth
some role, because both estradiol and testosterone appear to before epiphyseal closure occurs. Most of the time, the dom-
promote GH secretion. inant effect of sex steroids is to narrow the growth window,
In addition to these humoral influences, nutritional thereby diminishing ultimate longitudinal bone growth.
factors also modulate both GH secretion and IGF-1 produc- This effect is well illustrated in settings in which children are
tion. In both children and adults, GH secretion is triggered exposed to excessive sex steroid at an early age. The sex ste-
by high dietary protein intake. Teleologically, this is intrigu- roids can come from endogenous sources (e.g., early matu-
ing in that it may provide linkage between the availability of ration of the hypothalamic-pituitary-gonadal axis that
amino acids to serve as substrates for body protein synthesis produces premature puberty, or tumors that secrete estro-
(growth) and the endocrine stimulus of cells to grow. This gen or androgen) or from exogenous sources (e.g., children
relationship is not simple, however, because the rise in GH who take sex steroids prescribed for others). Again, the
levels in the setting of protein intake is not sufficient to growth curve is useful in that it typically shows an increase
stimulate IGF-1 production fully. This principle is well illus- in growth rate, followed by an early leveling off of growth
trated by fasting, which is associated with a decline in IGF-1 associated with the development of secondary sexual
even with increased GH. During fasting, insulin levels are characteristics.
low. Increased insulin appears to be required, at least in
some tissues, for GH to stimulate IGF-1 effectively. Glucocorticoids An excess of adrenal glucocorticoids
inhibits growth. In children who produce too much cortisol,
as a result of either adrenal or pituitary tumors (which
Thyroid hormones, steroids, and insulin also
produce adrenocorticotropic hormone [ACTH] and cause
promote growth
secondary increases in plasma cortisol), growth ceases. The
Although the discussion to this point emphasizes the action use of synthetic glucocorticoids in treating various serious
of GH and the GH-induced growth factors as modulators of illnesses (e.g., asthma, organ transplantation, various chronic
somatic growth, we could regard them as necessary but not autoimmune processes) also arrests growth. Restoration
sufficient agents for normal growth. Certain other hor- of normal growth does not occur until the glucocorticoid
mones, as well as receptive growth-responsive cartilage, are levels return toward normal. Neither GH nor IGF-1 concen-
required. Because growth is a difficult phenomenon to study, trations drop significantly during glucocorticoid treatment.
especially in humans (few scientists want to follow an experi- The failure of GH administration to correct the growth
ment over 10 to 20 years), much of our understanding of retardation that occurs in glucocorticoid-treated children
endocrine regulation of normal growth derives from obser- further confirms that GH deficiency cannot account for the
vations of abnormal growth as it occurs in clinical syndromes growth failure associated with glucocorticoid excess. Because
of endocrine excess or deficiency. Several of the more impor- linear growth is related to cartilage and bone synthesis
tant of these endocrine influences are illustrated here. The at the growth plates, glucocorticoids presumably are acting
exact mechanism by which growth is regulated by these at least in part at these sites to impair growth. However, the
agents is not always well understood. specific biochemical locus at which glucocorticoids act
remains unclear. In adults, as in children, glucocorticoid
Thyroid Hormones Next to GH, perhaps the most promi- excess impairs tissue anabolism and thus may manifest as
nent among the growth-promoting hormones are the thyroid wasting in some tissues (e.g., bone, muscle, subcutaneous
hormones thyroxine and triiodothyronine, which are dis- connective tissue), rather than growth failure. This tissue
cussed in Chapter 49. In many nonhuman species, thyroid wasting results in some of the major clinical morbidity of
hormone plays a major role in tissue growth and remodel- glucocorticoids (i.e., osteoporosis, muscle weakness, and
ing. For example, resorption of the tadpole tail during mor- bruising).
phogenesis requires thyroid hormone. In humans, deficiency In glucocorticoid deficiency, growth is not substantially
of thyroid hormones early in life can cause dwarfism or cre- affected. However, other deleterious effects of cortisol defi-
tinism (see Chapter 49). In children with normal thyroid ciency (e.g., hypoglycemia; see Chapter 51) dominate.
1038 Section VIII • The Endocrine System

Insulin This hormone is also an important growth factor, lowed by endochondral ossification. The calcified cartilage
particularly in utero. For example, women with diabetes is remodeled as it moves toward the metaphyses of the bone,
frequently have high blood levels of glucose during where it is eventually replaced by true lamellar and trabecu-
pregnancy and deliver babies of high birth weight (fetal lar bone (see Chapter 52). This process continues until
macrosomy). The developing fetus, exposed to glucose epiphyseal closure occurs toward the completion of
concentrations that are higher than normal, secretes addi- puberty.
tional insulin. Hyperinsulinemia results in increased fetal The process of cartilage formation and longitudinal bone
growth. Fetal macrosomy can create significant obstetric dif- growth begins as the cellular elements capable of forming
ficulties at the time of delivery. cartilage divide along the growth plate and then migrate
Conversely, infants born with pancreatic agenesis or with toward the more mature bone. These cells synthesize the
one of several forms of severe insulin resistance are very extracellular matrix of cartilage, which include type II colla-
small at birth. One form of this condition, leprechaunism, gen, hyaluronic acid, and mucopolysaccharides. These cells
is the result of a defect in the insulin receptor (see Chapter appear to respond directly to GH by proliferating and
51 for the box on this topic). Thus, it appears that insulin, increasing production of the extracellular matrix. This
acting through its own receptor, is an intrauterine growth response involves local generation of IGF-1 within the car-
factor. tilage as an early event in the growth process. As the cells
Severe insulin deficiency produces a marked catabolic more closely approach the already formed cortical and tra-
effect associated with wasting of lean body mass in both becular bone, ossification of the extracellular matrix begins,
children and adults. The acute adverse effects of such defi- and eventually the cellular elements become isolated by the
ciency (dehydration and acidosis) dominate the clinical calcifying cartilage. However, this calcified cartilage is not
picture. Milder degrees of insulin deficiency, seen in patients structurally the same as normal bone, and soon after forma-
with chronically undertreated diabetes, diminish growth in tion, it begins to be remodeled by an ingrowth of cellular
affected children. Improved diabetes management may allow elements (osteoclasts and osteoblasts) from adjacent bone.
restoration of normal growth rates and possibly even some Eventually, it is replaced by normal bone and becomes part
transient accelerated or catch-up growth. Thus, with good of the metaphysis of the long bone.
care, children with diabetes can expect to achieve normal In most children, growth ceases within several years after
adult height. completion of puberty, when the chondrocytes at the growth
plates of the long bones stop dividing and calcify the previ-
ously cartilaginous surrounding matrix. After puberty, radial
The musculoskeletal system responds to growth
growth occurs as bones increase their diameter through a
stimuli of the GHRH-GH–IGF-1 axis
process of endosteal bone resorption and periosteal bone
Longitudinal growth involves lengthening of the somatic deposition. This process is not strictly compartmentalized;
tissues (including bone, muscle, tendons, and skin) through that is, resorption and deposition of bone occur at both the
a combination of tissue hyperplasia and hypertrophy. Each periosteal and endosteal surfaces. However, during periods
of these tissues remodels its structure throughout life. For of growth, the rate of periosteal deposition exceeds the rate
bone, longitudinal growth occurs by the hyperplasia of of endosteal resorption, and the bone shafts grow in width
chondrocytes at the growth plates of the long bones, fol- and thickness.
As may be expected, numerous disorders disrupt the
complex process of endochondral bone growth on a genetic
or congenital basis (e.g., defects in collagen or mucopolysac-
Anabolic-Androgenic Steroids charide synthesis) and lead to genetic forms of dwarfism. In
these settings, the GHRH-GH–IGF-1 axis is entirely intact

W
e are all unfortunately familiar with the potential for and appears to regulate normally. No apparent compensa-
abuse of anabolic-androgenic steroids by body- tion occurs for the short stature by increased GH secretion,
builders and competitive athletes. Illicit use of these a finding suggesting that the axis is not sensitive to the
agents appears to be widespread in sports, where strength growth process per se, but simply to the intermediate chemi-
is closely linked to overall performance. In addition to natu- cal mediator IGF-1.
rally occurring androgens such as testosterone, dihydrotes- GH and IGF-1 clearly play important roles in mediating
tosterone, androstenedione, and dehydroepiandrosterone,
longitudinal bone growth and also modulate growth of other
many different synthetic androgenic steroids—as well as
tissues. Thus, proportional growth of muscle occurs as bones
GH—serve as performance enhancers. In addition to the
sought after “beneficial” effects of increasing muscle mass
elongate, and the visceral organs enlarge as the torso increases
and strength, each of these agents carries with it a plethora in size. The mechanisms by which GH and IGF-1 coordinate
of adverse side effects. Some—such as oily skin, acne, and this process and the way in which other hormones or growth
hair growth—are principally cosmetic. Others—including liver factors may be involved continue to be investigated. It is
function abnormalities, mood changes with aggressive clear that, whereas GH and, more recently, IGF-1 have been
behavior, and hepatocellular carcinoma—are much more considered the major hormones responsible for somatic
serious. Illicit use of these agents by younger athletes, espe- growth, other tissue growth factors play an important, albeit
cially teenagers, is also problematic with regard to alterations incompletely defined, role. Table 48-3 lists some of these
in growth and sexual maturation. growth factors. In general, the tissue growth factors have
more tissue-specific actions on organogenesis and their
 Chapter 48 • Endocrine Regulation of Growth and Body Mass 1039

Table 48-3 Other Growth Factors Affecting Growth intake and expenditure. If energy intake exceeds expenditure
over time—positive energy balance (see Chapter 58)—body
Nerve growth factor (NGF) mass will increase, assuming the diet is not deficient in
essential macronutrients or micronutrients. Small positive
Fibroblast growth factor (FGF) deviations from a perfect energy balance, over time, contrib-
ute to the major increase in body weight—the “obesity epi-
Angiogenesis factor
demic”—that afflicts many middle-aged adults, and
Vascular endothelial growth factor (VEGF) increasingly adolescents, in developed societies. For example,
if energy intake in the form of feeding exceeds energy expen-
Epidermal growth factor (EGF) diture by only 20 kcal (1 tsp of sugar) daily, over 1 year a
person would gain ~1 kg of fat and, over 2 decades,
Hepatocyte growth factor (HGF) ~20 kg.
Indeed, it is remarkable that many adults maintain a con-
sistent body weight for decades essentially in the absence of
conscious effort. Thus, a finely tuned regulatory system must
in some manner monitor one or more aspect of body mass,
growth-promoting activity than the IGFs, and they appear direct the complex process of feeding (appetite and satiety)
to act largely in a paracrine or autocrine fashion. to replete perceived deficiencies, and yet avoid excesses.

Energy expenditure comprises resting metabolic

REGULATION OF BODY MASS rate, activity-related energy expenditure, and
diet-induced thermogenesis
The multiple hormonal factors that influence longitudinal
growth—discussed in the previous two sections—are them- We can group energy expenditure into three components:
selves responsive to the nutritional intake of a growing indi-
vidual. For example, amino acids and carbohydrates promote 1. Resting metabolic rate (RMR). The metabolism of an
insulin secretion, and amino acids stimulate GH secretion. individual who is doing essentially nothing (e.g., sleep-
In addition, the availability of an adequate, balanced nutri- ing) is known as the RMR (see Chapter 58), which
ent supply likely exerts both direct and indirect influences amounts to ~2100 kcal/day for a 70-kg adult. The RMR
to promote tissue growth. Independent of any hormonal supports maintenance of body temperature, the basal
factors, glucose, fatty acids, and amino acids can each influ- functioning of multiple body systems (e.g., heartbeat,
ence the transcription of specific genes. Similarly, amino gastrointestinal motility, ventilation), and basic cellular
acids can directly activate the signaling pathways involved in processes (e.g., synthesizing and degrading proteins,
regulating mRNA translation. maintaining ion gradients, metabolizing nutrients).
Beyond the effects of macronutrients, micronutrients can 2. Activity-related energy expenditure. As we wake up in
be similarly important in regulating cell growth and, by the morning and begin to move about, we do more than
extension, growth of the organism. An example is iodine, a resting metabolism. Exercise or physical work can have a
deficiency of which can produce dwarfism (see Chapter 49). major impact on total daily energy expenditure and varies
In a more global fashion, the effect of nutrient limitation on widely across individuals and within an individual on a
height can be appreciated by considering the differences in day-to-day basis. We also expend energy in activities not
mean height between men in North Korea (165 cm) and classically regarded as exercise or heavy work—tapping
South Korea (171 cm). As mentioned in Chapter 49, nutri- our foot while sitting in a chair, looking about the room
tional deprivation early in life can markedly limit longitudi- during physiology lecture, typing at a keyboard—
nal growth. Perhaps equally fascinating, and only recently activities dubbed non–exercise-associated thermogenesis
appreciated, is that nutritional deprivation early in life also or NEAT. Such energy expenditures can vary 3- to 10-fold
appears to predispose affected individuals to obesity when across individuals and can account for 500 kcal or more
they reach middle age. This phenomenon was first noted in of daily energy expenditure. NEAT differences, over
epidemiologic studies from several European countries that time, could considerably contribute to differences in
revealed a positive correlation between middle-aged obesity weight gain by individuals consuming identical caloric
and being born during periods of deprivation during and intake.
immediately following the Second World War. Such find- 3. Diet-induced thermogenesis. Eating requires an addi-
ings suggest that some level of genetic programming occurs tional component of energy expenditure for digesting,
early in life that both diminishes longitudinal growth and absorbing, and storing food. Typically, diet-induced ther-
predisposes persons to body mass accretion. mogenesis accounts for 10% of energy expenditure. Pro-
teins have a higher thermic effect than either carbohydrates
or fats.
The balance between energy intake and
expenditure determines body mass
Each of these three components of energy expenditure
At any age or stage of life, the factors that govern body mass can vary considerably from day to day and is subject to regu-
accretion relate specifically to the energy balance between lation. For example, thyroid hormone is a major regulator
1040 Section VIII • The Endocrine System

of thermogenesis (see Chapter 49). Overproduction of mouse (Fig. 48-8B), the wild-type mouse starved. Finally, in
thyroid hormone increases both RMR and NEAT, whereas parabiosis experiment connecting an Ob/Ob to a Db/Db
thyroid hormone deficiency has the opposite effect. mouse (Fig. 48-8C), the Ob mouse lost weight, but the Db
mouse remained obese. These results indicate that (1) the
Db mouse makes an excess of the blood-borne factor that
Hypothalamic centers control the sensations of
cures the Ob mouse, (2) the Db mouse lacks the receptor
satiety and hunger
for this factor, and (3) the absence of the receptor in the Db
Classic studies—in which investigators made lesions in, or mouse removes the negative feedback, thus leading to high
electrically stimulated, specific brain regions—identified two levels of the blood-borne factor.
areas in the hypothalamus that are important for controlling In 1994, Jeffrey Friedman and his colleagues used posi-
eating. A satiety center is located in the ventromedial nucleus tional cloning to identify leptin (from the Greek leptos
(VMN; see Fig. 47-3). Electrical stimulation of the satiety [thin]), the blood-borne factor lacked by Ob mice. Leptin is
center elicits sensations of satiety, even when an animal is in a 17-kDa protein made almost exclusively in adipocytes. The
the presence of food. Conversely, a lesion of the satiety replacement of leptin in Ob/Ob mice leads to rapid weight
center causes continuous food intake (hyperphagia) even in loss. In 1995, Tepper and collaborators cloned the leptin
the absence of need. A hunger (or feeding) center is located receptor (Ob-r). The deficiency of this receptor in Db mice
in the lateral hypothalamic area (LHA; see Fig. 47-3). Electri- makes them leptin resistant. Ob-r is a tyrosine kinase–asso-
cal stimulation of this center elicits a voracious appetite, even ciated receptor (see Fig. 3-11D) that signals through JAK-2
after an animal has ingested adequate amounts of food. A and STAT (see Fig. 4-15).
lesion of the hunger center causes complete and lasting ces- Although leptin acts on numerous tissues within the
sation of food intake (aphagia). body, most importantly it somehow crosses the blood-brain
barrier (see Chapter 11) and modulates specific neurons in
the arcuate nucleus of the hypothalamus that control feeding
Leptin tells the brain how much fat is stored
behavior. These same neurons also have insulin receptors.
Only in the last decade have we begun to understand regula- Plasma leptin levels in humans appear to rise in proportion
tory mechanisms that maintain body mass, made possible to the mass of adipose tissue. Conversely, the absence of
by the study of mouse models of obesity. One monogenic leptin produces extreme hyperphagia, as in Ob/Ob mice.
model is the Ob/Ob strain of hyperphagic mice that develop Plasma leptin has a half-time of ~75 minutes, and acute
morbid obesity; affected mice typically weigh > 100% more changes in food intake or fasting do not appreciably affect
than unaffected animals of the same strain. In parabiosis leptin levels. In contrast, insulin concentrations change dra-
experiments, in which an Ob/Ob mouse was surgically con- matically throughout the day in response to dietary intake.
nected to a wild-type mouse (Fig. 48-8A), the Ob/Ob mouse Thus, it appears that leptin in some fashion acts as a long-
lost weight, a finding suggesting that such mice lack a blood- term regulator of CNS feeding behavior, whereas insulin (in
borne factor. Another model of monogenic obesity is the addition to multiple other factors) is a short-term regulator
(Db/Db) mouse, named Db because it secondarily develops of the activity of hypothalamic feeding centers.
type 2 diabetes. These mice are hyperphagic, with adult body In addition to its actions in controlling appetite, leptin
weights ~100% higher than those of lean littermates. In promotes fuel utilization. Indeed, leptin-deficient humans
parabiosis experiments connecting a Db/Db and a wild-type paradoxically exhibit some characteristics of starvation (e.g.,
fuel conservation).

A B C
Leptin and insulin are anorexigenic (i.e., satiety)
signals for the hypothalamus
At least two classes of neurons within the arcuate nucleus
Ob Db Ob Db contain receptors for both leptin and insulin. These neurons,
in turn, express neuropeptides. One class of neurons pro-
duces pro-opiomelanocortin (POMC), whereas the other
produces neuropeptide Y (NPY) and agouti-related protein
(AgRP).

POMC Neurons Both insulin and leptin stimulate the

POMC-secreting neurons (Fig. 48-9), which produce
POMC (see Fig. 50-4). At their synapses, POMC neurons
release a POMC cleavage product, the melanocortin α-
melanocyte–stimulating hormone (α-MSH), which, in turn,
A = Ob mouse + Wt mouse binds to MC3R and MC4R melanocortin receptors on
B = Db mouse + Wt mouse second-order neurons. Stimulation of these receptors not
C = Ob mouse + Db mouse only produces satiety and decreases food intake—that is, α-
Figure 48-8 Parabiosis experiments. In parabiotically coupled MSH is anorexigenic (from the Greek a [not] + orexis [appe-
mice, ~1% of the cardiac output of one mouse goes to the other, tite])—but also increases energy expenditure through
and vice versa, so that the animals exchange blood-borne factors. activation of descending sympathetic pathways. An indica-
 Chapter 48 • Endocrine Regulation of Growth and Body Mass 1041

Higher CNS Food

centers
Eating
behavior

NTS
Glucose-
HYPOTHALAMUS sensitive
PVN neurons

D LHA
M
N

VMN

ARC

Ghrelin

Fa
sti
Short-term

ng
feedback
Anorexigenic Orexigenic
neuron neuron Distention
(POMC/CART) (AGRP/NPY) of GI tract
stimulates
vagal afferents.

Stretch
Long-term
feedback Feeding
Leptin CCK

Adipocyte Intestinal cells

secrete CCK.

Glucose
Lipid
Insulin Fats
storage
Amino
acids Small intestine absorbs
foodstuffs, transferring
them to blood.

Figure 48-9 Control of appetite. ARC, arcuate nucleus.

tion of the importance of this pathway is that ~4% of indi- NPY/AgRP Neurons In addition to stimulating POMC
viduals with severe, early-onset obesity have mutations in neurons, both insulin and leptin also suppress neurons in
MC3R or MC4R. POMC neurons also synthesize another the arcuate nucleus that release NPY and AgRP at their
protein—CART or cocaine-amphetamine–related tran- synapses (Fig. 48-9). NPY activates NPY receptors—pre-
script, which, like α-MSH, is anorexigenic. dominantly Y1R and Y5R, which are GPCRs—on secondary
1042 Section VIII • The Endocrine System

neurons, thus stimulating eating behavior. AgRP binds to 4. Paraventricular nucleus (PVN). This nucleus contains
and inhibits MC4R melanocortin receptors on the secondary neurons that, in turn, project to both cerebral cortex and
neurons in the POMC pathway, thereby inhibiting the areas of the brainstem (see Fig. 47-3).
anorexigenic effect of α-MSH. In other words, both NPY 5. Nucleus tractus solitarii (NTS). This nucleus integrates
and AgRP are orexigenic. The yellow obese or agouti mouse sensory information from the viscera (see Chapter 2) and
overexpresses the agouti protein, which inhibits melanocor- also receives input from paraventricular neurons.
tin receptors. Overinhibition of MC1R on melanocytes
inhibits the dispersion of pigment granules (leading to yellow
Ghrelin is an orexigenic signal for
rather than dark fur). Overinhibition of MC3R and MC4R
the hypothalamus
on anorexigenic neurons blocks the action of α-MSH
(leading to obesity). Signals originating from the periphery can be not only
The secondary neurons to which the POMC and NPY/ anorexigenic (i.e., promoting satiety)—as in the case of leptin
AgRP neurons project are in five major locations (Fig. 48-9 (from adipose tissue) and insulin (from the pancreas)—but
and also see Fig. 47-3): also orexigenic (i.e., promoting appetite). One of these is
ghrelin, made in response to fasting by specialized endo-
1. LHA. In this hunger center, NPY/AgRP neurons crine cells in the gastric mucosa. Indeed, systemically admin-
stimulate—but POMC neurons inhibit—secondary istered ghrelin acutely increases food intake when it is given
neurons producing the orexigenic peptides melanin- at physiological doses in both animals and humans. Circu-
concentrating hormone (MCH) or orexins A and B. lating ghrelin concentrations, however, appear to be lower
2. VMN. This nucleus is a satiety center. in obese than lean humans, a finding suggesting that ghrelin
3. Dorsomedial hypothalamic nucleus (DMN). does not drive the increased caloric intake in the obese.

Human Obesity

O
ne approach for gauging the extent to which human levels of the hormone. In the other two thirds of obese persons,
body mass is appropriate for body height is to compute the leptin resistance is so severe that they fail to respond even
the body mass index (BMI): to the exogenous hormone. Lean persons lose weight in
response to leptin.
Weight in kg In addition to mutations to the leptin gene, two other
BMI =
(Height in m)2 extremely rare mutations cause monogenic human obesity.
One is mutation of the leptin receptor gene (analogous
BMIs fall into four major categories: to the Db mouse) and the other is mutation of the POMC
gene (leading to loss of the anorexigenic α-MSH). A more
1. Underweight: less than 18.5 common—although rare—cause of monogenic human obesity
2. Normal weight: 18.5 to 24.9 is a mutation in the melanocortin MC4 receptor, the target of
3. Overweight: 25 to 29.9 α-MSH.
4. Obesity: 30 or more Currently, no satisfactory pharmacological approaches are
available to treat obesity. Of the two agents currently approved
Although a BMI of 30 or more is an indication of obesity, it in the United States by the Food and Drug Administration, one
is not a direct measure of adipose tissue fat mass. Obesity is is a serotonin re-uptake inhibitor and one blocks fat digestion
an area of intense investigation driven in part by the “obesity and therefore absorption within the gastrointestinal tract.
epidemic” that is adversely affecting the health of a large frac- Neither agent directly intervenes at targets within the hypotha-
tion of the population of developed nations. lamic neuroendocrine control system (Fig. 48-9). More impor-
The demonstration that replacement of leptin in Ob/Ob tantly, each is limited by side effects, and each is only minimally
mice led to rapid weight loss raised considerable enthusiasm effective in decreasing weight. Perhaps more promising, but
for the potential of leptin as a pharmacological agent in the still being tested, are antagonists of the cannabinoid receptors
treatment of human obesity. Indeed, several extremely rare (CB-1 and CB-1), which are GPCRs. These drugs decrease
individuals had been identified with autosomal recessive body weight by blocking access of endogenously produced
monogenic obesity secondary to leptin deficiency, like the arachidonic acid derivatives known as endocannabinoids,
Ob/Ob mouse. As expected, these individuals respond to which are ligands of CB-1 and CB-2. These receptors are
exogenous leptin administration with a marked reduction in located in many areas throughout the brain, as well as in
body weight. However, investigators soon appreciated that peripheral tissues. They are richly represented in the basal
most obese persons are not leptin deficient. Quite the contrary, hypothalamus as well as within the nucleus accumbens in the
human plasma leptin concentrations increase proportionately limbic system. CB blockers appear to be effective in achieving
to BMI, which is a rough estimate of adipose tissue fat mass. and maintaining meaningful weight reduction (10 to 20 kg) for
Although obese persons generally are not leptin deficient, more than 1 year. The same agents are also effective in
approximately one third of obese persons lose weight in decreasing smoking behavior. Investigators are still unraveling
response to exogenous leptin. These individuals are leptin how blocking the cannabinoid receptor affects the output of
resistant, but they eventually respond to sufficiently high hypothalamic neurons that regulate appetite.
 Chapter 48 • Endocrine Regulation of Growth and Body Mass 1043

However, gastric bypass procedures in morbidly obese mass are cortical control (e.g., “will power”) and environ-
patients cause ghrelin levels to decline dramatically along ment (e.g., the availability of high-calorie foods). Our emerg-
with decreases in body weight and food consumption. ing appreciation of the biological basis of obesity may allow
As discussed previously, ghrelin binds to GHSR, which is a more scientific and clinical approach to therapeutic inter-
present in neurons of the arcuate nucleus as well as vagal ventions—rather than simply blaming affected patients for
afferents. Some hypothalamic neurons themselves contain their obesity.
ghrelin, and injection of ghrelin into the cerebral ventricles
stimulates feeding. It is not clear to what extent circulating
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