Hormonal Regulators of Appetite

Abstract

Obesity is a significant cause of morbidity and mortality worldwide. There has been a significant worsening of the obesity epidemic mainly due to alterations in dietary intake and energy expenditure. Alternatively, cachexia, or pathologic weight loss, is a significant problem for individuals with chronic disease. Despite their obvious differences, both processes involve hormones that regulate appetite. These hormones act on specific centers in the brain that affect the sensations of hunger and satiety. Mutations in these hormones or their receptors can cause substantial pathology leading to obesity or anorexia. Identification of individuals with specific genetic mutations may ultimately lead to more appropriate therapies targeted at the underlying disease process. Thus far, these hormones have mainly been studied in adults and animal models. This article is aimed at reviewing the hormones involved in hunger and satiety, with a focus on pediatrics.

Full text

Hindawi Publishing Corporation
International Journal of Pediatric Endocrinology
Volume 2009, Article ID 141753, 9pages
doi:10.1155/2009/141753
Review Article
Hormonal Regulators of Appetite
Juliana Austin and Daniel Marks
Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, Portland, OR 97239, USA
Correspondence should be addressed to Juliana Austin, austinju@ohsu.edu
Received 11 November 2008; Accepted 18 November 2008
Recommended by Scott A. Rivkees
Obesity is a significant cause of morbidity and mortality worldwide. There has been a significant worsening of the obesity epidemic
mainly due to alterations in dietary intake and energy expenditure. Alternatively, cachexia, or pathologic weight loss, is a significant
problem for individuals with chronic disease. Despite their obvious differences, both processes involve hormones that regulate
appetite. These hormones act on specific centers in the brain that affect the sensations of hunger and satiety. Mutations in these
hormones or their receptors can cause substantial pathology leading to obesity or anorexia. Identification of individuals with
specific genetic mutations may ultimately lead to more appropriate therapies targeted at the underlying disease process. Thus far,
these hormones have mainly been studied in adults and animal models. This article is aimed at reviewing the hormones involved
in hunger and satiety, with a focus on pediatrics.
Copyright © 2009 J. Austin and D. Marks. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
1. Introduction
Obesity is a significant cause of morbidity and mortality
in the US and worldwide. Obesity in adults and children
increases the risk of type 2 diabetes mellitus [1], cardiovas-
cular disease [2], and nonalcoholic fatty liver disease [3], as
well as psychosocial and social disturbances [4]. Significantly,
obese children have an increased likelihood of becoming
obese adults compared with children who are not obese [5].
And the incidence of childhood obesity is rising: during
2003-2004, 17.1% of children (<20 years) had body mass
indexes (BMIs) ≥95% for age and sex [6]. Increases in
weight in the pediatric population are on the rise; by the
year 2010, almost 50% of North American children and
38% of European children are expected to be overweight
[7]. This forecast represents a long-term trend: surveys since
1963 have documented increasing numbers of overweight
and obese children, and the rate of increase is accelerating
[8,9]. Overweight children were heavier in 1998 compared
with 1986 [10]. Not surprisingly, BMI has also continued to
increase with a shifting of the normal population bell-shaped
curve to the right.
At the other end of the spectrum, children with chronic
diseases are significantly affected by weight loss, or cachexia,
that includes “pathologic wasting of either muscle or muscle
and fat tissue” [11]. Key features of cachexia include anorexia
or decreased appetite despite weight below the physiologic
set point, an accelerated loss of lean body tissues, and
lack of a protective decrease in basal metabolic rate as
weight continues to be lost. Cachexia has been found to
be associated with such chronic illnesses as congenital heart
disease [12], Crohn disease [13], renal failure [14,15], and
cancer [16,17]. While the underlying cause of cachexia
in chronic disease is complex, most authors agree that
increased production of proinflammatory cytokines leads to
many of the pathological features observed in this condition
[18]. These cytokines interact directly and indirectly with
centers in the brain that control appetite and basal metabolic
rate and also have important direct effects on peripheral
tissues.
Although great progress has been made in understanding
the hormonal players that regulate appetite in adults, and
therefore contribute to obesity and its opposite cachexia,
these insights have not yet been applied to the pediatric
population. This article will review the key hormonal players
involved in hunger and satiety and how these hormones
directly affect the brain. We will also review how humans
and animals with mutations in these hormones or their
receptors develop substantial pathology. Such mutations may
increase the risk of developing obesity or disease-associated

2 International Journal of Pediatric Endocrinology
Tab le 1
Hunger Hormone Primary location of
production Receptors Action
Hypothalamus
NPY Medial arcuate nucleus
(also widespread in CNS) Y1, Y5 Stimulating feeding and antagonizing POMC
actions
AgRP Medial arcuate nucleus MC3R and MC4R
antagonist Stimulating feeding
Peripheral peptides
Ghrelin Stomach GHS-R1a Stimulating feeding by increasing NPY/AgRP
and antagonizing leptin effects
Satiety
Hypothalamus
POMC/α-MSH Arcuate nucleus MC3R and MC4R Inhibiting feeding, stimulating basal metabolic
rate, and altering nutrient partitioning
CART Arcuate nucleus Inhibiting feeding
Peripheral peptides
CCK Duodenum, jejunum CCK-A, CCK-B
Inhibiting feeding and Stimulating pancreatic
secretion, gall bladder contraction, intestinal
motility, and inhibition of gastric motility
PYY Ileum, colon, rectum Y2 Inhibiting feeding by inhibition of NPY and
stimulation of POMC
PP Endocrine pancreas Y4, Y5 Inhibiting feeding
Oxyntomodulin Distal ileum and colon GLP-1 receptor
Inhibiting gastric acid secretion, decreasing
gastric emptying, and decreasing pancreatic
enzyme secretion
GLP-1 Distal ileum and colon GLP-1 receptor
Delaying gastric emptying, stimulating
glucose-dependent insulin secretion, inhibiting
glucagon secretion, and stimulating
somatostatin secretion
GIP Stomach, duodenum,
jejunum GIP receptor
Glucose-dependent insulin secretion,
induction of βcell proliferation, promotion of
energy storage, enhancement of bone
formation
Insulin Endocrine pancreas Insulin receptor Inhibiting feeding
Leptin Adipose tissue Leptin receptor,
Ob-Rb
Inhibiting NPY and AgRP and Stimulating
POMC and CART
Adiponectin Adipose tissue Adipo R1, R2 Inhibiting feeding
cachexia. Finally, we will discuss how hormone replacement
or supplementation can offer a therapeutic option for obesity
or cachexia. Much work has been done in adults and animal
models. Here, we will attempt to address how these insights
might affect pediatric practice and highlight the importance
in children.
2. Hunger
2.1. The Role of the Hypothalamus in Stimulating Appetite.
The hypothalamus acts as the control center for hunger and
satiety. Part of the hypothalamus, the arcuate nucleus (or,
in humans, the infundibular nucleus), allows entry through
the blood-brain barrier of peripheral peptides and proteins
that directly interact with its neurons. These include neurons
that coexpress peptides that stimulate food intake and
weight gain, specifically, neuropeptide Y (NPY) and agouti-
related peptide (AgRP), as well as those expressing pro-
opiomelanocortin (POMC) and cocaine- and amphetamine-
regulated transcript (CART) which inhibit feeding and
promote weight loss (see Tabl e 1). Together, these neurons
and peptides control the sensations of hunger and satiety and
ultimately weight gain and weight loss.
NPY is part of the pancreatic polypeptide (PP-)fold
peptide family (NPY, polypeptide YY (PYY), PP). The medial
arcuate nucleus contains the NPY neurons which project to
the paraventricular nucleus, hypothalamic nucleus, lateral
hypothalamic area, and other hypothalamic sites. NPY
synthesis and release are regulated by leptin and insulin (both
inhibitory), and glucocorticoids and ghrelin (both stimu-
latory), among many other factors. The most noticeable
physiological response to central administration of NPY is
the stimulation of feeding [19]. NPY initiates appetite drive

International Journal of Pediatric Endocrinology 3
through the NPY G-protein coupled receptors (primarily
Y1 and Y5). NPY also represses the anorexigenic effect of
melanocortin signaling in the arcuate. In the hypothalamus,
NPY is one of the most abundant peptides and one of the
most potent orexigenic factors.
AgRP is produced by neurons located within the medial
arcuate nucleus that coexpress NPY. AgRP in humans
has sequence similarity to the agouti signaling protein in
mice. The agouti protein is a paracrine-signaling molecule
produced normally in the skin that inhibits the effect
of α-melanocyte stimulating hormone (α-MSH) on the
melanocortin-1 (MC-1) receptor [20]. Overexpression of
agouti signaling protein in mice leads to yellow coat color by
blocking α-MSH at the MC-1 receptor. These mice are also
obese, insulin resistant, hyperglycemic, and have increased
body length [21]. This is because AgRP, an endogenous
antagonist (and inverse agonist) of melanocortin-3 and
melanocortin-4 receptors, is implicated in control of energy
balance [22]. Blockage of these receptors leads to stimulation
of feeding.
2.2. The Peripheral Peptide that Stimulates Appetite. Cir-
culating peptides also play important roles in appetitive
behaviors. Of these, ghrelin, or growth hormone (GH)-
releasing peptide, is the only known circulating orexigen, or
appetite stimulant. It is mainly produced by the endocrine
cells of the gastric mucosa of the fundus, but is also found in
much smaller amounts in other tissues, including the small
intestine, pituitary gland, hypothalamus, pancreas, lung,
immune cells, placenta, ovary, testis, and kidney. Ghrelin
levels rise prior to meals, then fall quickly after ingestion of
nutrients [23]. Thus it is postulated that one primary role of
ghrelin is to act as a meal initiator.
The ghrelin receptor, GH secretagogue receptor type
1a (GHS-R1a), is a G-protein coupled receptor that is
widely expressed. Within the CNS, it is found in areas
involved in the regulation of appetite and energy balance,
including the hypothalamic nuclei, dorsal vagal complex,
and mesolimbic dopaminergic system. Ghrelin has multiple
effects, including stimulation of GH, ACTH, cortisol, aldos-
terone, catecholamine, and prolactin secretion. Exogenous
ghrelin administration has also been found to affect glucose
homeostasis, gut motility, pancreatic exocrine secretion,
cardiovascular function, immunity, and inflammation [24].
Intracerebroventricular administration of ghrelin in rats
leads to increased food intake, excess weight gain, and
adiposity [25]. Similarly, administration of ghrelin to obese
and lean human subjects leads to increased food intake [26].
Ghrelin leads to this increase of food intake and body weight
in part by stimulating the production of NPY and AgRP
in the arcuate nucleus [27]. Ghrelin may also alter energy
balance by stimulating adipogenesis, inhibiting apoptosis,
transitioning from fatty acid oxidation to glycolysis for
energy expenditure, and inhibiting sympathetic nervous
system activity [28–31].
Globally, ghrelin levels reflect nutritional status and body
fat stores. Ghrelin levels in humans are inversely correlated
with adiposity, being low in obese subjects, higher in lean
subjects, and markedly elevated in subjects with cachexia
due to cancer and chronic cardiac failure, as well as those
in starvation states such as anorexia nervosa [32–37]. An
exception to this is Prader-Willi syndrome, where, despite
obesity, affected individuals have high levels of fasting and
postprandial ghrelin [38]. Ghrelin treatment in rats has
been shown to improve weight gain and lean body mass
retention in cancer cachexia and chronic kidney disease
[39,40], offering a potential therapy for cachexia in humans.
Alternatively, future studies may examine ghrelin antagonists
as a therapeutic option for obesity.
3. Satiety
3.1. The Role of the Hypothalamus in Regulating Appetite.
The hypothalamus is also the master regulator of satiety,
via production of POMC and CART. The POMC gene is
expressed by multiple tissues, including the skin and immune
system, as well as the pituitary gland and the arcuate nucleus
of the hypothalamus. POMC undergoes tissue-specific post-
translational cleavage, with the product depending on the
endoproteases expressed in that tissue. For example, in the
anterior pituitary gland, POMC is primarily converted to
ACTH by prohormone convertase 1. In mammals other
than primates, prohormone convertase 2 in the intermediate
pituitary cleaves ACTH to yield α-melanocyte stimulating
hormone (α-MSH) that is involved in the control of coat/skin
color. With respect to the hypothalamus in humans, leptin (a
peptide produced by adipose tissue) is thought to stimulate
POMC conversion into α-MSH in the arcuate nucleus.
The neurotransmitter in turn binds to the melanocortin-4
receptor (MC4R), a key receptor involved in appetite control
and energy homeostasis, in the paraventricular nucleus and
in numerous other sites throughout the brain. Intracere-
broventricular administration of α-MSH in rodents inhibits
feeding and reduces body weight. As previously mentioned,
AgRP is an antagonist of MC4R. Thus, mice overexpressing
AgRP or MC4R knockout mice are hyperphagic and obese
[41] and are insensitive to α-MSH.
MC4R mutations have been found in up to 5.8% of adults
with severe childhood-onset obesity [42]. POMC deficiency
also leads to obesity (due to lack of binding at MC4R),
hypocortisolism (due to lack of binding of ACTH to the
MC2R in the adrenal gland), and alteration of pigment (due
to lack of binding at MC1R in the skin). This syndrome is
defined by severe early onset obesity, adrenal insufficiency,
and red hair [43]. Accordingly, in rodent models of cancer
and renal failure, MC4R receptor antagonists attenuate
symptoms of cachexia by maintaining appetite, lean body
mass, and basal energy expenditure [44]. Thus, MC4R
antagonists may be a useful clinical treatment of cachexia
[45], while agonists are being developed to treat obesity.
Another important satiety regulator in the hypothalamus
is cocaine- and amphetamine-regulated transcript (CART),
which is coexpressed with POMC in arcuate neurons in
animal models and somewhat paradoxically with AgRP
and NPY in humans [46]. Similar to POMC neurons,
CART neurons are directly stimulated by leptin [47]. CART
neurons target areas throughout the hypothalamus and are

4 International Journal of Pediatric Endocrinology
associated with reinforcement and reward [48], sensory
processing, and stress and endocrine regulation [47,49].
Animals deprived of food have decreased the expression
of CART mRNA [47]. Along those same lines, blocking
CART with an antiserum increases feeding in normal rats
[50]. Intracerebroventricular administration of CART in rats
inhibits normal and starvation-induced feeding, as well as
blocking the NPY feeding response [47,50]. At this point, we
are not aware of any clinical trials utilizing CART agonists
or antagonists for weight regulation perhaps due to the
significant nonappetite effects associated with CART.
3.2. Peripheral Peptides Known to Control Satiety. In contrast
to ghrelin, the single peripheral peptide known to stimulate
hunger, there are many peripheral peptides that are asso-
ciated with satiety. Various organs secrete these hormones,
including the gastrointestinal tract, pancreas, and adipose
tissue. The list of satiety hormones is far too extensive
to discuss in this review. We will, therefore, focus on the
key players starting with cholecystokinin (CCK), the first
discovered satiety hormone.
Cholecystokinin (CCK) was initially discovered in 1928
and was one of the first peptides to be found in the gut
[51]. In addition to inhibiting food intake, CCK stimulates
pancreatic secretion, gall bladder contraction, intestinal
motility, and inhibition of gastric mobility. Administration
of CCK to rats inhibits food intake by reducing meal size and
duration [52], which is enhanced by gastric distention [53].
The half-life of CCK is only 1-2 minutes, therefore it is not
effective at reducing meal size if administered more than 15
minutes before a meal [52].
CCK is synthesized throughout the gastrointestinal tract,
but mainly in the duodenum and jejunum. Multiple bioac-
tive forms are derived from the same gene product by
posttranslational or extracellular processing. CCK is rapidly
released locally and into the circulation in response to
nutrients in the gut, especially fat and protein, with a gradual
increase in levels over 10–30 minutes after meal initiation,
remaining elevated for up to 5 hours [54].
CCK-sensitive brain sites include the lateral hypotha-
lamus, medial pons, and lateral medulla. These areas are
involved in reward behavior, memory and anxiety, as well as
satiety [55,56]. There are two types of G-protein coupled
CCK receptors: CCK-A and CCK-B [57]. CCK-A is involved
in satiety whereas CCK-B is not. CCK-A is found on the
afferent vagal neurons that have a direct effect on food intake.
Rats deficient in CCK-A (Otsuka Long Evans Tokushima
Fatty (OLETF) rats) are hyperphagic, obese, and develop
diabetesmellitustype2[58].
Another satiety peptide, peptide YY (PYY), is part of
the pancreatic polypeptide (PP-) fold peptide family (NPY,
PYY, PP), all of which have 36 amino acids, contain several
tyrosine residues, and require C-terminal amidation for
biologic activity. The PP-fold family exerts their effects via
the Y family of G-protein coupled receptors (Y1, Y2, Y4, Y5)
that are expressed in the hypothalamus. PYY is produced
by the intestinal L cells of the ileum, colon, and rectum.
Following food intake, PYY is released into the circulation
and peaks 1-2 hours postprandially [59]. PYY concentrations
are proportional to meal energy content and are therefore
higher after fat intake compared to carbohydrates and
proteins [60]. Circulating PYY exists in two forms: PYY1-36
and PYY3-36. PYY3-36 is the peripherally active anorectic
signal and is created by cleavage of the N-terminal Tyr-Pro
residues by dipeptidyl peptidase IV (DPP-IV) [61]. PYY3-36
binds to Y2 receptors leading to inhibition of NPY neurons
and stimulation of POMC neurons.
Administration of PYY delays gastric emptying, inhibits
secretions from the pancreas and stomach, inhibits gall-
bladder contraction, and increases the absorption of fluid
and electrolytes from the ileum [62]. In rodents, the
administration of PYY decreases food intake and reduces
weight gain [63], as well as, improves glycemic control
in rodent models of diabetes [64]. PYY-deficient mice are
resistant to satiety and develop marked obesity, which is
reversed by exogenous PYY administration [65]. In contrast,
intracerebroventricular administration of full length PYY
stimulates food intake. This is thought to be via action on Y1
and Y5 receptors in the paraventricular nucleus, the neurons
targeted by the orexigenic arcuate nucleus NPY neurons.
In obese and lean humans, administration of PYY3-36
decreases food intake with a significant decrease in the
cumulative 24 hour caloric intake [66]. Obese subjects, how-
ever, have a lower endogenous PYY response at each meal
compared to normal weight volunteers [67]. This relative
PYY deficiency may reduce satiety and could thus reinforce
obesity. Obese patients treated by jejunoileal bypass surgery
[68] or vertical-banded gastroplasty [69] have elevated PYY
levels, which may contribute to their appetite loss.
Pancreatic polypeptide (PP), another member of the PP-
fold peptide family, is produced largely in the endocrine
pancreas, and also in the exocrine pancreas, colon, and
rectum. PP is also released in response to a meal, in
proportion to caloric load, and inhibits appetite [70]. PP
release is stimulated by ghrelin, as well as motilin (a peptide
secreted by the small intestine that enhances gastrointestinal
motility) and secretin (a peptide secreted by the duodenum
that stimulates gastric acid secretion), whereas somatostatin
(a hormone that decreases the rate of gastric emptying,
and reduces smooth muscle contraction and blood flow
within the intestine) and its analogs significantly reduce
PP secretion. PP binds with greatest affinity to the Y4
and Y5 receptors [71]. Peripheral administration of PP in
normal mice reduces food intake, gastric emptying, and
gastric expression of ghrelin, while it increases vagal tone
[72]. Similar to PYY, injection of PP into the third ventricle
stimulates daytime food intake [73]. Interestingly, patients
with Prader-Willi syndrome have suppressed basal and
postprandial PP levels [74]. Administration of PP in Prader-
Willi patients leads to reduced food intake [75].
Incretins are hormones released from the gastrointestinal
tract into the circulation in response to nutrient ingestion.
Incretins enhance glucose-stimulated insulin secretion. Pre-
proglucagon is expressed in the αcells of the endocrine
pancreas, L cells of the intestine (distal ileum and colon), and
neurons located in the caudal brainstem and hypothalamus.
It is cleaved into multiple different products, including

International Journal of Pediatric Endocrinology 5
glucagon and two of the incretins, oxyntomodulin and
glucagon-like peptide-1 (GLP-1). Oxyntomodulin and GLP-
1 are released from L cells in the distal ileum and colon
in response to ingestion of nutrients. Oxyntomodulin binds
the GLP-1 receptor that is expressed in the nucleus of the
solitary tract in the brainstem and in the arcuate nucleus.
Oxyntomodulin inhibits gastric acid secretion, decreases
gastric emptying, and decreases pancreatic enzyme secretion
which is likely related to decreased gastric output [76].
Administration of oxyntomodulin in humans has been
found to suppress ghrelin levels [77], decrease body weight
and appetite, decrease leptin, and increase adiponectin levels
presumably secondary to loss of adipose tissue [78].
GLP-1 leads to delay in gastric emptying, stimulation of
glucose-dependent insulin secretion, inhibition of glucagon
secretion, and stimulation of somatostatin secretion. GLP-
1 binds to its receptor, a G-protein coupled receptor that
belongs to the class B family, including receptors for glucagon
and GIP [79]. The GLP-1 receptor is expressed in a wide
range of tissues, including the pancreatic islet cells, lung,
heart, kidney, stomach, intestine, pituitary, skin, vagus nerve,
and several regions of the CNS including the hypothalamus
and brainstem. Peripheral and central GLP-1 administration
activates neurons in the arcuate and paraventricular nuclei,
nucleus of the solitary tract, and area postrema [80] leading
to decreased appetite. GLP-1 administration promotes sati-
ety and has beneficial effects on glucose homeostasis.
The properties of GLP-1 have made it a useful drug
target. GLP-1 is released rapidly into the circulation after
oral nutrient ingestion, and its secretion occurs in a biphasic
pattern starting with an early (within 10–15 minutes) phase
that is followed by a longer (30–60 minutes) phase [81].
The half-life of GLP-1 is less than 2 minutes owing to
rapid inactivation by the enzyme DPP-IV, which also cleaves
PYY. This is the basis for the development of exenatide
(Byetta), a subcutaneously administered DPP-IV-resistant
GLP-1 receptor agonist.
Glucose-dependent insulinotropic polypeptide (GIP) is
another incretin that is secreted by the stomach and K
cells in the duodenum and jejunum in response to nutrient
ingestion. The half-life of GIP is 7 minutes in healthy
individuals and 5 minutes in patients with type 2 diabetes
[82]. GIP is also inactivated by DPP-IV [82,83]. The GIP
receptor gene is expressed in the pancreas, stomach, small
intestine, adipose tissue, adrenal cortex, pituitary, heart,
testis, endothelial cells, bone, trachea, spleen, thymus, lung,
kidney, thyroid, and several regions in the CNS. GIP leads
to glucose-dependent insulin secretion, induction of βcell
proliferation, promotion of energy storage via direct actions
on adipose tissue, and enhancement of bone formation
via stimulation of osteoblast proliferation and inhibition of
apoptosis. In the CNS, GIP is expressed in the hippocampus
and GIP receptor expression is detected in the cerebral
cortex, hippocampus, and olfactory bulb. GIP action in the
CNS may play a role in neural progenitor cell proliferation
and behavior modification [84].
Insulin is another hormonal regulator of appetite. Insulin
levels increase rapidly after a meal and vary directly with
changes in adiposity. Insulin penetrates the blood-brain
barrier via a saturatable, receptor-mediated process at levels
proportional to the circulating insulin [85]. Insulin receptors
are widely distributed in the brain with highest concen-
trations found in the olfactory bulbs and arcuate nucleus.
Once insulin enters the brain, it acts as an anorexigenic
signal [86]. Mice with a neuron-specific disruption of the
insulin receptor gene have increased food intake, obesity with
increased body fat, and plasma leptin levels, and impaired
spermatogenesis and ovarian follicle maturation [87]. There
are several insulin receptor substrates (IRS) that are activated
by phosphorylation by the insulin receptor on their tyrosine
residues [88]. IRS-1 and IRS-2 have been identified in
neurons. IRS-2 knockout mice have been found to have
increased food intake, increased fat stores, and infertility
[89].
Leptin, also termed OB protein, is another important
appetite regulator. It is produced by the white and brown
adipose tissue, stomach, placenta, mammary gland, ovarian
follicles, and certain fetal organs such as heart, bone or
cartilage, and perhaps the brain. The ob gene is expressed in
all adipose tissue, but to a greater degree in the subcutaneous
adipose tissue than the omental fat. Leptin levels are posi-
tively correlated with the amount of body fat mass. Leptin
secretion does not appear to be driven by meal patterns.
Instead, the circadian pattern is characterized by high levels
between midnight and early morning hours and a nadir
around noon to midafternoon [90]. Leptin is secreted in a
pulsatile fashion with 32 peaks per 24-hour period and a
pulse duration of 32.8 minutes [91]. This implies that neural
and neurohormonal components in the brain may regulate
leptin secretion from adipocytes.
Leptin receptors belong to the cytokine receptor super-
family, which uses the Janus activating kinase (JAK-) signal
transducer and activator of transcription (STAT) pathway of
signal transduction. Leptin receptors have multiple different
splice variants. Ob-Rb is the long form of the receptor and
has a long intracellular domain, which is necessary for the
action of leptin on appetite. Ob-Rb is expressed in multiple
different sites within the hypothalamus including the arcuate
nucleus, paraventricular nucleus, dorsomedial hypothalamic
nucleus, and lateral hypothalamic area. Short forms of the
Ob receptor may play a role in the transport of leptin across
the blood-brain barrier [92]. After binding the receptor,
leptin stimulates a specific signaling cascade that results
in inhibition of orexigenic peptides (NPY and AgRP) [93,
94], while stimulating anorectic peptides (including POMC
and CART) [93,95]. Ultimately, this leads to decreased
appetite and increased energy expenditure. db/db mice
have a mutation in the intracellular portion of Ob-Rb and
therefore are unable to respond to the leptin signal and
as a result develop profound obesity [96]. Additionally, it
has been found that up to 3% of individuals with severe
early onset obesity have pathogenic mutations in the leptin-
receptor gene [97].
Ob-deficient mice have an absence of circulating leptin
and develop severe obesity due to both increased food
intake and decreased energy expenditure [98], both of which
can be normalized by the administration of leptin [99].
The absence of leptin in humans leads to severe obesity,

6 International Journal of Pediatric Endocrinology
hypogonadism, and impaired T cell mediated immunity,
which are remediable with administration of recombinant
leptin [100]. About 5% of obese populations are “relatively”
leptin deficient and it is possible that these individuals could
benefit from leptin therapy [101].
Finally, the hormone adiponectin is secreted by the
mature adipocyte. Adiponectin receptors are expressed in the
brain, particularly in the paraventricular nucleus, amygdala,
area postrema, and diffusely in the periventricular areas.
For reasons that are unclear, adiponectin’s concentration
in the blood stream is extremely high, approximately 1000
times higher than that of other polypeptide hormones.
Its structure closely resembles C1q and types VIII and
X collagen. Generally, adiponectin self associates to form
homotrimers that then dimerize to yield hexamers. Increased
adiponectin levels in rodents appear to decrease body fat
mass by stimulation of fatty acid oxidation in muscle [102].
Adiponectin also decreases food intake and obesity in obese
rats [103], and improves insulin sensitivity by decreasing
hepatic glucose output [104]. In humans, high molecular
weight adiponectin (which is thought to be the active form)
is reduced in patients with type 2 diabetes, and increasing the
proportion of high molecular weight adiponectin by weight
loss and treatment with thiazolinediones leads to improved
insulin sensitivity [105].
4. Suggestions in Children
Although the obesity epidemic has worsened significantly in
children presumably owing to alterations in dietary intake
and energy expenditure, there have been clearly demonstra-
ble genetic mutations in hormones and their receptors that
may be implicated in childhood obesity. It would therefore
be important to identify children with early onset obesity
that is resistant to dietary modification and physical activity
to evaluate them for possible genetic mutations. This could
lead to more appropriate therapies targeted at the underlying
disease process. It has also become clear that certain acquired
pathological states associated with childhood obesity may
respond well to specific-targeted therapy based on the
underlying pathology. For example, the intense hyperphagia
and weight gain frequently observed after damage of the
basal hypothalamus (e.g., commonly observed after resection
of a craniopharyngioma) may be due to the loss of the
inhibitory tone provided by POMC neurons. In this case,
treatment with a melanocortin agonist may be particularly
beneficial. In contrast, patients with Prader-Willi syndrome
may be more likely to benefit from therapies that restore
normal physiological levels of peripheral appetite regulating
hormones, such as ghrelin antagonists.
Similarly, one might also consider hormonal agonists or
antagonists as treatments of cachexia. Several preclinical and
clinical trials indicate that GHS-1 R agonists (including ghre-
lin itself) are effective agents for this particular metabolic
derangement. Other models suggest that melanocortin-
4 receptor antagonists will also provide effective therapy
for cachexia and involuntary weight loss. Collectively, our
understanding of the complex nature of weight regulation
has opened the door to a more thoughtful approach to
therapeutic intervention in disorders of weight regulation.
The redundancy of these systems highlights the likelihood
that no one single agent will be effective in every situation,
making individualized combinations of therapy a more
rational solution to weight regulation therapy.
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