Chapter

Neuroendocrine Regulation of Appetite and

4 Body Weight

Anorexia nervosa and obesity constitute two extremes up to 50% of adults deemed overweight, and 29% of
of dysfunctional body weight control. Anorexia ner- obese adults – as determined by BMI – were cardiome-
vosa is characterized by low body weight and global tabolically healthy. For example, heavily muscled indi-
endocrine abnormalities, especially of the viduals with increased body weight will have BMI
hypothalamic–pituitary axis, as well as altered adipo- values that may be interpreted as overweight or obese.
kine function and appetite-regulating hormone levels Conversely, 30% of individuals classified as healthy by
(Schorr and Miller, 2017). These same systems are BMI scores were in fact metabolically unhealthy
implicated in the pathology of obesity. How the (Dhurandhar, 2016; Tomiyama et al., 2016). This mis-
brain regulates appetite and body weight has become classification prompted the suggestion that excess body
a vital public health issue, often described as a global fat – largely deposited in the abdominal region – may
obesity epidemic (Schwartz et al., 2017). Obesity is be a superior indicator of metabolic ill health
strongly associated with a decrease in the quality of (Maffetone et al., 2017).
life and an escalating incidence of cardiovascular dis- A prevailing perspective is that obesity is caused
ease, type 2 diabetes, osteoarthritis, certain cancers, by individual greed and self-indulgence in the face of
hypertension, stroke and Alzheimer’s disease (World an abundance of hyperpalatable, energy-dense and
Obesity Federation, 2017; Goodarzi, 2018). low-cost food, as well as a sedentary lifestyle.
A comprehensive and detailed study, assembling Fundamentally, the pathogenesis of obesity appears
data from 195 countries, examined the prevalence of to be straightforward: calories are consumed in
overweight and obesity among children and youth (<20 amounts that exceed ongoing energy expenditure.
years of age) and adults between 1980 and 2015 Nonetheless, not all people faced with such abun-
(The GBD Obesity Collaborators, 2017; see also NCD dance eat too much or become obese and there are
Risk Factor Collaboration, 2017). Based on body mass now efforts to regard obesity as a disease (Editorial,
index (BMI) measurements (weight in kg/height in m2) 2017; World Obesity Federation, 2017). Considerable
a total of 107.7 million children and 603.7 million progress has been made in our understanding of the
adults were obese (BMI>30) in 2015. High BMI was neuroendocrine pathways that regulate appetite and
responsible for 4.0 million deaths globally. the control of body weight, and it is also clear that
The prevalence of obesity has doubled since 1980 in pronounced genetic components may sometimes
more than 70 countries, and increased in many others. underlie a susceptibility to becoming overweight and
In Canada, for example, recent statistics indicate that obese (Yeo, 2017). For example, studies in twin pairs
6.9 million people (>18 years of age) are obese and and in adopted children revealed that a large percen-
9.4 million are overweight (BMI=25–29) (Stats tage of the risk for obesity is heritable (Stunkard et al.,
Canada, 2017). In the United Kingdom, in 2015, 58% 1990; Schwartz et al., 2017). The search for specific
of women and 68% of men were overweight or obese genes through genome-wide analysis revealed more
(GOV.UK, 2017). The United States has the highest than 100 sites (loci) associated with BMI, as well as
incidence of childhood obesity (12.7%). The World strong support for hypothalamic genes that underlie
Obesity Federation estimates that the global cost of regulation of body mass and the susceptibility to obe-
treating obesity-related illnesses will approach US$1.2 sity (Locke et al., 2015; Pigeyre et al., 2016). More than
trillion per year by 2025. Notwithstanding these alarm- 30 obesity syndromes are known, and gene mutations
ing figures, it is worth noting that the use of BMI as for leptin, leptin receptor, melanocortin-4 receptor
a risk indicator of health may be questionable; that is, (MC4 R) and pro-opiomelanocortin (POMC) induce 53

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Figure 4.1 Obesity and the

incidence of some common
chronic diseases. Adapted and
redrawn from the original
(World Obesity Federation,
2017).

hyperphagia and obesity (Heymsfield and Wadden, humans, weight gain as a result of forced over-
2017). Although rare, these examples will be used in eating inhibits the rewarding aspects of food while
the following sections to provide insights into human enhancing satiety, resulting in reduced food intake,
appetite control (see Section 4.3). increased energy expenditure and a return to nor-
mal body weight (Schwartz et al., 2017).
In contrast, food deprivation induces central adap-
4.1 The Neural Control of Appetite tive responses that amplify the rewarding proper-
The major neural centers for the regulation of ties of food and desensitizes the response to satiety
appetite are located in the hypothalamus and signals. The net result is an increase in food con-
brain stem. Although our present understanding sumption (Morton et al., 2014).
of this system is inevitably based on animal experi- Figure 4.3 illustrates in more detail some of the
ments, these control pathways appear to largely hypothalamic neurochemical pathways known to reg-
conform to the available knowledge from human ulate food intake (Schwartz and Morton, 2002).
data. Figure 4.2 outlines in general terms the The clinical relevance of these systems will be
homeostatic regulation of food intake. The brain, described in the following sections, and a case will
and especially the hypothalamus, integrates signals be described illustrating hypothalamic lesion-induced
(e.g., leptin) from adipose tissue (long-term energy hyperphagia (see Uher and Treasure, 2005).
storage) and short-term meal-related signals An informative online poster (Dietrich and
(nutrients, and gut-derived hormones such as Horvath, 2010) illustrates much of the information to
54 ghrelin) to regulate food intake. In normal-weight follow: http://www.nature.com/nrn/posters/feeding.

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Leptin Deficiency
Reward
The crucial importance of leptin in the control of
body weight is revealed in humans carrying mutations
Food intake Satiety
that effectively produce leptin deficiency; that is,
either mutations in the leptin gene – that reduce
biologically active leptin – or in the leptin receptor
gene that abolish the effects of leptin. Mutations in the
Nutrient related Short-term
satiety signals leptin receptor signaling pathway are also known, and
Ghrelin these will be described in Section 4.3.
Adiposity-related
(long term) Blood
glucose GLP-1
Mutations in the leptin gene are rare, but affected
PYY
CCK
3–36
children are severely obese and exhibit intense hyper-
phagia and aggressive behavior when food is denied.
Liver
The earliest patients discovered with leptin gene muta-
Stomach
tions had no circulating leptin and they responded to
Insulin CCK leptin treatment with a remarkable reduction in fat
Leptin GI tract
GLP-1
levels and body weight (in children: Farooqi et al.,
Adipose
tissue PYY3–36
2002; Farooqi and O’Rahilly, 2014; in adults: Licinio
et al., 2004). Rather than mutations in the leptin gene,
Figure 4.2 Hormonal and nutrient regulation of food intake. a complete deletion of the gene has also been reported
The brain, and especially the hypothalamus, integrates signals from
long-term energy stores (e.g., leptin from adipose tissue) and short- (Ozsu et al., 2017). This child was grossly obese by the
term meal-related signals (nutrients, and gut-derived satiety signals age of 6 months and exhibited intense hyperphagia.
such as ghrelin) to regulate food intake. Overfeeding inhibits the The effect of leptin deficiency in children is revealed in
rewarding properties of food while enhancing meal-induced satiety,
thereby reducing food intake. In response to energy deprivation, Figure 4.4.
central adaptive responses are engaged that increase the rewarding Other clinical features include high rates of child-
properties of food and reduce the response to satiety signals,
collectively resulting in increased food consumption until deficient
hood infection, hyperinsulinemia, type 2 diabetes as
fat stores are replenished. Reproduced with permission (Morton adults, hypothyroidism (low thyroxine [T4], high thyr-
et al., 2014). Abbreviations: CCK, cholecystokinin; GI, gastrointestinal; oid stimulating hormone [TSH]), absence of puberty
GLP-1, glucagon-like peptide-1; PYY3-36, peptide YY. and hypogonadotropic hypogonadism. The assay of
serum leptin levels would seem to be an effective test
in patients with severe early-onset obesity; an undetect-
4.2 Leptin: A Fat-Derived Peptide able serum leptin level being suggestive of congenital
Hormone leptin deficiency. However, another form of leptin gene
Adipose tissue is a large endocrine organ that secretes mutation leads to high levels of immunoreactive serum
a new family of hormones called adipokines leptin that has no biological activity; that is, it does not
(Fasshauer and Blüher, 2015). This section will focus bind to leptin receptors (Wabitsch et al., 2015).
on leptin as the prototypical adipokine, although Treatment of these patients with recombinant human
many more adipokines have now been identified leptin normalized weight loss and eating behavior.
(Beall et al., 2017). Since its discovery in 1994, leptin A similar clinical picture is seen in patients with
has generated thousands of publications and is impli- a mutation in the leptin receptor; that is, signaling at
cated in many neural, reproductive, metabolic, the mutant receptor is impaired, so that these patients
immune, endocrine and neuroendocrine systems are effectively leptin free even though leptin levels are
(Farooqi and O’Rahilly, 2014; Friedman, 2016). The high (Farooqi et al., 2007). They are also characterized
generally accepted view of leptin’s mode of action is by severe obesity, hyperphagia, abnormal immune func-
its ability to reduce food intake and to maintain body tion and delayed puberty due to hypogonadotropic
fat levels. It does this by instructing the hypothalamus, hypogonadism. The elevated serum leptin levels are
which contains leptin receptors, to reduce appetite typical of the obese state and reflect the increase in fat
and increase energy expenditure (Figure 4.3). mass.

55

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Neuron

NPY
α–MSH Food Energy
intake expenditure
INCREASE AgRP
APPETITE

DECREASE
APPETITE
NPY
NPY/ Arcuate
AgRP nucleus

Third POMC
ventricle
Melanocortin (MC4R)
– receptor for MSH
+
–
+ Ghrelin
GHRELIN
PYY3–36 STOMACH PYY/GLP-1/CCK
GLP-1
INSULIN
CCK AMYLIN NPY
LEPTIN
Insulin or leptin or
amylin

GI TRACT Duodenum
PANCREAS
ADIPOSE
TISSUE

Figure 4.3 Neuroendocrine control of food intake. The figure illustrates the crucial role of the hypothalamic arcuate nucleus in regulating food
intake. Leptin and insulin (co-released with amylin) circulate in the blood at concentrations proportional to body fat mass. They decrease
appetite by inhibiting neurons that produce the molecules NPY and AgRP, at the same time stimulating α-MSH (POMC) neurons in the arcuate
nucleus. NPY and AgRP stimulate eating, and α-MSH inhibits eating, via other neurons (top). Activation of NPY/AgRP-expressing neurons
inhibits POMC neurons, either directly through NPY receptors or by AgRP blocking the effects of α-MSH. The hormone ghrelin stimulates
appetite by activating the NPY/AgRP-expressing neurons. PYY3-36 and GLP-1, released from the small intestine, inhibit these neurons and
thereby decrease appetite. Reproduced with permission (Schwartz and Morton, 2002). Abbreviations: AgRP, agouti-related peptide; CCK,
cholecystokinin; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; MSH, melanocyte-stimulating hormone; NPY, neuropeptide Y; POMC, pro-
opiomelanocortin; PYY, peptide YY.

Leptin and Amenorrhea gonadotropin secretion. This may also be true in

Leptin deficiency – in terms of low serum levels – is leptin-treated adult leptin-deficient males, where tes-
also encountered in certain conditions where the lep- tosterone and free testosterone reached normal adult
tin gene is functional and leptin receptors are normal. values along with the appearance of secondary sexual
For example, anorexia nervosa patients have abnor- characteristics (Paz-Filho et al., 2015). In women with
mally low serum leptin levels, as do some patients an intact leptin gene, and in the absence of organic
with hypothalamic amenorrhea. The critical impor- disease or ovarian failure, hypothalamic amenorrhea is
tance of leptin for normal reproductive function was most commonly associated with stress, weight loss or
clearly demonstrated in those leptin-deficient chil- intense athletic exercise (see Section 3.3). Such condi-
dren described earlier (Figure 4.4). Leptin treatment tions disrupt normal neuroendocrine processes,
resolved the problems of hyperphagia and obesity but, induce premature osteoporosis, decrease fat mass
significantly, allowed these children to enter puberty and reduce serum leptin levels, resulting in anovula-
and to exhibit pulsatile gonadotropin secretion (Chou tion (Chou and Mantzoros, 2014; Paz-Filho et al.,
and Mantzoros, 2014; Farooqi and O’Rahilly, 2014). 2015). In two clinical trials, leptin replacement in
The assumption here is that leptin had a positive effect amenorrheic women reduced body weight and fat
56 mass and significantly elevated luteinizing hormone
on the hypothalamic regulation of pituitary
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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

human leptin increases nocturnal LH secretion in

patients with lipodystrophy, suggesting that leptin has
a direct effect on the hypothalamic–pituitary system
(Abel et al., 2016).

Obesity and Leptin Excess

In contrast to those obese patients with deficient leptin –
that is, because of leptin gene mutations (see earlier in
the chapter) – obesity in the general population is
characterized by increased serum leptin levels due to
the enlarged adipose tissue mass. Figure 4.6A illustrates
that serum leptin concentrations are positively corre-
lated with percent of body fat and are significantly
higher in obese compared with normal-weight indivi-
duals (31.3+/-24.1 vs. 7.5+/-9.3 ng/mL; p<0.001;
Considine et al., 1996; see also Sahin-Efe et al,. 2017).
This figure also includes the different percent body fat
range in males and females (Guerra et al., 2008).
Figure 4.4 Leptin treatment of an obese child. Left panel, a 3-year- Figure 4.6B illustrates that women have significantly
old boy with congenital leptin deficiency (body weight: 42 kg). higher leptin levels than do men (x3.4; p<0.05); in both
On the right, the same boy, after four years of daily subcutaneous
injections of recombinant human leptin. Leptin induced a striking sexes leptin levels are proportional to fat mass and BMI
decrease in body fat (body weight: 32 kg). Reproduced with (p<0.001; Guerra et al., 2008).
permission (Farooqi and O’Rahilly, 2014). The data in Figure 4.6A imply that obese indivi-
duals are insensitive to their own leptin; that is, high
(LH), LH pulse frequency and estradiol concentra- levels of leptin secretion fail to reduce food intake or
tions. The effect of leptin on LH secretion in two body weight. By analogy with the insulin resistance
amenorrheic patients is illustrated in Figure 4.5 seen in type 2 diabetes, the common forms of diet-
(Welt et al., 2004). Evidence of ovulation and related obesity are thought to be attributable to “leptin
increased bone health in some patients confirm the resistance,” a state in which multiple cellular pro-
involvement of the hypothalamus (Chou and cesses block leptin receptor signaling (Myers et al.,
Mantzoros, 2014; Kyriakidis et al., 2016). 2010). The phenomenon of leptin resistance suggests
that leptin treatment of obesity is unlikely to be
Lipodystrophy and Leptin Deficiency a therapeutic option. This proved to be correct.
Lipodystrophy – the complete or partial absence of fat Consistent with an earlier study (Heymsfield et al.,
tissue – is a rare disorder associated with severe insulin 1999), treatment of overweight and obese men and
resistance, diabetes and hyperphagia (Fiorenza et al., women (n=284) for 12 weeks with twice-daily injec-
2011). Most patients with generalized lipodystrophy tions of leptin failed to induce meaningful weight loss
are leptin-deficient and physiological replacement (Zelissen et al., 2005).
doses of leptin induce improvements in insulin sensi- However, one component of leptin resistance is
tivity, glucose tolerance and levels of fasting glucose believed to be leptin’s inability to penetrate the
(Paz-Filho et al., 2015). Lipodystrophic patients also blood–brain barrier to reach hypothalamic leptin
exhibit reproductive dysfunction such as amenorrhea, receptors. This problem may be amenable to clinical
reduced fertility, polycystic ovarian syndrome, hyperan- intervention through development of leptin analogs
drogenism (in adults) and central hypogonadism in that improve access of leptin to the central nervous
children (Brown et al., 2016). Recombinant human system (Yi et al., 2014; Rhea et al., 2017). A further
leptin treatment of adult women with this syndrome promising approach, and one which has shown clin-
decreased free testosterone levels, improved insulin sen- ical utility already (see later in this chapter), is to take
sitivity and induced normal menstruation (Musso et al., advantage of the known anorexigenic properties of
2005). It is possible that leptin replacement acts on the gut peptides such as glucagon-like peptide-1 (GLP-
neuroendocrine hypothalamus; that is, recombinant 1) and amylin (see Figure 4.3). 57

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Figure 4.5 Representative patterns of pulsatile LH secretion in two leptin-treated amenorrheic women. Subjects had secondary hypothalamic
amenorrhea for 6 months or more. BMI values were in the normal range (18–24 kg/m2). Leptin treatment (recombinant human leptin) was self-
administered (0.08 mg/kg; daily, subcutaneous). Panel A shows a non-pulsatile pattern (two subjects) at baseline, which improved to
a normal or low-frequency pattern during 2 weeks of leptin treatment. Panel B shows a low-frequency pattern (four subjects) before treatment,
which improved to normal during treatment. Pulses of LH are indicated by asterisks. Data obtained from Welt et al. (2004).

Leptin and Gut Peptides in Control of Appetite and Body subjects, the combination of recombinant human lep-
Weight tin and the amylin analog pramlintide significantly
The ability of amylin – co-released with insulin from induced weight loss compared to leptin or pramlin-
the pancreas (Figure 4.3) – to control appetite and tide alone (Figure 4.7).
body weight in experimental animals is well
described, but this type of peptide may also be clini- 4.3 Other Genetic Forms of Obesity
cally useful (Hay et al., 2015). This topic will be cov- We have seen that mutations in the leptin gene, or
ered in more detail in subsequent sections (see leptin receptor gene, have profound effects on body
Section 4.4), but the successful use of amylin is weight. Other monogenic mutations in the hypotha-
described here. In contrast to the lack of effect of lamic leptin–melanocortin pathway, although rare,
leptin in reducing body weight, the combination of constitute experiments of nature that confirm the
leptin with an amylin agonist induced significant critical importance of this signaling pathway in the
weight loss in obese subjects (Ravussin et al., 2009; control of appetite. For example, since POMC neu-
58 Tam et al., 2011). In a 24-week, randomized, double- rons decrease appetite through the release of α-
blind, proof-of-concept study in obese or overweight melanocyte-stimulating hormone (α-MSH) that
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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

A final example illustrates a contemporary

approach to identifying genes implicated in the induc-
tion of obesity. The sequencing of the human genome
has permitted gene-mapping studies – called genome-
wide association studies – that revealed a new gene
robustly linked to human obesity. This is the fat mass
and obesity related (FTO) gene (Loos and Yeo, 2014).

POMC Deficiency
First reported in 1998, children with mutations of the
POMC gene were deficient in α-MSH and adrenocor-
ticotropin (ACTH) peptides that are normally pro-
duced from cleavage of the POMC propeptide (see
Chapter 5; Figure 5.4) (Krude et al., 1998; Krude and
Grüters, 2000). The absence of ACTH resulted in
adrenal insufficiency, whereas the lack of α-MSH led
to pale skin and red hair, reflecting absent stimulation
of melanocytes in the skin and hair follicles. Life-
threatening adrenal insufficiency was treated with
hydrocortisone. The loss of α-MSH, and the subse-
quent signaling deficit at hypothalamic MC4 R recep-
tors, induced early-onset obesity and hyperphagia.
Subsequent reports have confirmed this early study
(Mendiratta et al., 2011; Çetinkaya et al., 2018).
An important approach in treating this syndrome
was the attempt to use hormone-replacement therapy;
that is, to reverse the α-MSH deficiency by stimulating
hypothalamic MC4 R with a synthetic MC4 R agonist,
setmelanotide (Kühnen et al., 2016; Reitman, 2016),
which is significantly more potent than the endogen-
Figure 4.6 Variation of leptin levels with percentage body fat (A) and
ous neuropeptide α-MSH (Collet et al., 2017). Two
fat mass/sex (B). (A) illustrates the dependence of serum leptin on the patients with POMC deficiency (BMI values: 54.1 and
percentage of body fat in 136 normal-weight and 139 obese 49.8 kg/m2) were markedly hyperphagic and obese
subjects. Plotted with data obtained from Considine et al. (1996). (B)
reveals the positive relationship between serum leptin levels and fat
(Figure 4.8A). Treatment with setmelanotide (subcu-
mass, but also shows that leptin levels are higher in women taneous, daily) over 40 weeks (patient #1) and 12
compared with men (p<0.05; men, n=34; women, n=33). Data weeks (patient #2) induced a large, sustained reduc-
obtained from Guerra et al. (2008).
tion in hunger scores and in body weight (Figure 4.8B
& 4.8C). In addition, a marked darkening of the skin
binds to the MC4 R receptor (Figure 4.3), mutations and hair was observed. Both patients reported
in the POMC gene or in the MC4 R gene are likely to a dramatic improvement in their quality of life after
affect food intake. initiation of treatment. Also shown is the rapid, but
In this section examples of these two mutations will reversible, change in weight gain and hunger during
be described: first, patients with a mutation in the a brief (3 weeks) off-treatment phase in patient #1.
POMC gene have early-onset obesity and severe hyper- Although this proof-of-principle study involved
phagia because of the lack of α-MSH; second, patients only two patients, it confirmed the fundamental
with MC4 R mutations who are insensitive to α-MSH importance of the leptin–melanocortin pathway in
are also obese and hyperphagic. Also included in this regulating human body weight and appetite.
section is an example of a multigenic disorder – A significant clinical question, given the apparent
Prader–Willi syndrome (PWS) – which is the most lack of serious side effects of this drug treatment, is
common cause of syndromic obesity. whether other forms of obesity might also be reversed 59

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Figure 4.7 Weight loss with leptin/amylin treatment in obese/

overweight subjects. Absolute change in body weight (kg) from
enrollment (4 weeks) in three groups (BMI values approx.
32 kg/m2): recombinant human leptin, n=19; pramlintide,
n=38; pramlintide/leptin, n=36. Values are means ±SEM. **
p<0.01 for combination treatment vs. leptin or pramlintide
alone. Data obtained from Ravussin et al. (2009).

A. Pre-therapy weight of the two patients B. Patient 1 during treatment

160 0 10

150 Off-treatment
phase 8

Hunger score
140 –20
6
130
120 4
Patient 1 –40
110 2
100
Body Weight (kg)

–60 0
Patient 2 90 0 10 20 30 40 50
80 Week of treatment

97th 70 C. Patient 2 during treatment

0 10
percentile
e 60
–5 8
50th 50 Hunger score
percentile
e
40 –10 6
30
–15 4
20
–20 2
10

0 –25 0
1 2 4 6 8 10 12 14 16 18 0 5 10 25
Age (yr) Week of treatment

Figure 4.8 Obesity in POMC deficiency treated with an MC4 R agonist, setmelanotide. (A) illustrates the body weight changes in two POMC-
deficient girls in the first 18 and 17 years of life, compared with the normal percentiles of girls of the same age. (B) shows the weight change
and hunger scores (on a scale of 0=no hunger, to 10=extreme hunger) in patient #1 during treatment with setmelanotide. After the initial 13
weeks of treatment, this patient entered a 3-week off-treatment phase before treatment was restarted. Note the rapid change in hunger score
60 and a 4.8 kg increase in body weight. These changes were reversed on re-instatement of treatment. (C) shows similar weight change and
hunger scores in patient #2 during 12 weeks of therapy. Data obtained from Kühnen et al. (2016).
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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

by MC4 R agonists (Müller et al., 2016). The following and TSH deficiencies, central adrenal insufficiency
section indicates that setmelanotide does induce (CAI) and hypogonadotropic hypogonadism.
weight loss in obese patients. It remains unknown whether the critical
leptin–melanocortin pathway is in any way responsi-
MC4R Deficiency ble for the obesity in PWS, although several reports
MC4 R deficiency is the most common known cause indicate that leptin levels are elevated, probably
of monogenic obesity. About 150 naturally occurring reflecting leptin resistance in these children. For
MC4 R gene mutations have been identified, and the example, in a large group of PWS patients (ages 7
prevalence of these mutations varies from 0.5 to 5.8% months–5 years) fasting plasma leptin levels were
in obese children and is around 2.3% in obese adults significantly higher compared to controls (Goldstone
(Valette et al., 2013). Some, but not all, of these chil- et al., 2012). The missing chromosome 15q11-q13
dren exhibited mealtime hyperphagia (Valette et al., contains a large number of genes of unknown func-
2014). In addition to severe obesity, patients had tion (Angulo et al., 2015).
increased lean mass, increased linear growth and Clinical implications: Hormonal assessment in
severe hyperinsulinemia (Farooqi et al., 2003). patients with PWS includes testing for GH deficiency,
The incidence of obesity was more severe in patients hypogonadism, adrenal insufficiency, hyperglycemia
with complete loss as opposed to partial loss of func- and osteoporosis. Treatment with human GH has
tion of MC4 R, indicating that control of human body been shown to increase linear height, improve body
weight is sensitive to quantitative variations in the composition by reducing adiposity and improve bone
level of functional MC4 R. quality (Bakker et al., 2017). Hypogonadism is com-
In a 28-day Phase 1b clinical trial, Collet et al. (2017) mon in PWS and may be associated with cryptorchid-
tested the hypothesis that setmelanotide treatment (sti- ism in boys. Treatment with human chorionic
mulation of MC4 R receptors) would induce weight loss gonadotropin has been shown to improve cryptorch-
in MC4 R-deficient patients; that is, by “rescuing” sig- idism (Bakker et al., 2015); additionally, treatment
naling by mutant MC4 R receptors. Their results with sex steroids is given to induce puberty and
showed a significant weight loss in patients with improve bone mass. A high prevalence of CAI in
MC4 R deficiency, and in obese controls. No changes PWS was reported (de Lind van Wijngaarden et al.,
were seen in heart rate or blood pressure, and other 2008), although others have not found a high risk of
adverse events were generally mild and well tolerated. CAI (Farholt et al., 2011). If identified, CAI should be
In a separate short-term study on obese patients, set- treated with glucocorticoid-replacement therapy and
melanotide successfully increased resting energy expen- expert opinion from a pediatric endocrinologist
diture (Chen et al., 2015). Overall, these data suggest should be sought.
that setmelanotide, by targeting the MC4 R receptor, is
a promising drug candidate for the treatment of obesity. The FTO Gene
The initial report on FTO identified a common gene
Prader–Willi Syndrome variant that predisposed patients to type 2 diabetes.
PWS is the most common syndromic obesity disor- It soon became obvious that this was mediated
der, affecting both sexes at similar rates, with esti- entirely through effects on BMI (Frayling et al.,
mates of annual prevalence of 1 in 10,000 to 1 in 2007). This was not detectable at birth, but was evi-
30,000 live births. Infantile hypotonia and failure to dent by the age of 7 years and persisted through
thrive are typical, followed by obesity and hyperpha- adulthood into old age. Several variants are now
gia in childhood (Angulo et al., 2015; Irizarry et al., known and are associated with substantial changes
2016). PWS occurs through a lack of multiple pater- in BMI, hip circumference and body weight (Scuteri
nally inherited genes on chromosome 15q11.2-q13, et al., 2007; Tung et al., 2014). Some reports, although
resulting in features such as short stature, develop- not all, link the FTO gene with increased energy
mental delay, cognitive disability and behavioral pro- intake, elevated intake of dietary fat, increased appe-
blems. Hypothalamic dysfunction is likely responsible tite and impaired satiety (Tung et al., 2014; reviewed
for obesity/hyperphagia, faulty temperature control, in Speakman, 2015).
high pain threshold, hypersomnia and multiple endo- Even though there is compelling genetic evidence
crine abnormalities including growth hormone (GH) that FTO gene variants are associated with increased 61

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

BMI, the mechanisms by which they lead to increased contraction/relaxation of smooth muscle walls and
eating behavior and obesity remain unknown. sphincters, and secretion of fluids and electrolytes.
However, FTO gene expression is enriched in human Even anticipation of a meal causes secretion of some
brain, especially in hypothalamus and cortex (Frayling hormones, and the mechanical and chemical stimula-
et al., 2007), suggesting that FTO expression is found tion of the stomach and intestine, caused by the pre-
in a brain location appropriate for appetite and body sence of food, induces release of hormones from the
weight control. In this regard, a more specific mechan- GI tract.
istic link has been established between FTO variants Figures 4.2 and 4.3 summarize how some of these
and circulating levels of the gut hormone ghrelin (see peptides target the hypothalamus. Ghrelin (from the
Section 4.4). Ghrelin is known to be orexigenic and stomach) is the only peptide illustrated that is orexi-
appears to be regulated by FTO (Karra et al., 2013). genic, the rest – GLP-1 and peptide YY (PYY; from
In brief, this report suggests that in response to eating, the small intestine), cholecystokinin (CCK; from the
people with an FTO obesity-risk gene variant fail to duodenum) and amylin (from the pancreas) – inhibit
suppress their hunger and circulating ghrelin levels; appetite and are therefore anorexigenic. Note that
that is, food intake suppressed circulating ghrelin these peptides represent variable short-term signals
levels in control subjects, whereas the same caloric triggered by eating patterns. In contrast leptin, for
load failed to suppress ghrelin appropriately in the example, exerts a long-term regulation that reflects
patients carrying the FTO mutation. In a subsequent adipose tissue stores.
study, in much older individuals, an overnight fast The following sections will focus on two clinically-
significantly elevated ghrelin levels in FTO variant relevant peptides that influence food intake in
carriers compared to controls (Benedict et al., 2014). humans: ghrelin (orexigenic) and GLP-1 (anorexi-
In summary, mutations in the FTO gene may genic). GLP-1, together with glucose-dependent insu-
encourage weight gain by affecting hormonal signals, lin releasing polypeptide (GIP), is an incretin
such as ghrelin, that stimulate appetite. However, an hormone released in humans in response to nutrient
influence of FTO on peripheral targets, such as adi- ingestion and serves to potentiate the glucose-induced
pose tissue, cannot be ruled out (Yang et al., 2017). insulin response (Gautier et al., 2008).
A more detailed appreciation of the interaction GIP will not be discussed further other than to
between FTO and its neural/peripheral targets may point out that GIP is implicated in a distinct but rare
offer new therapeutic approaches to reverse the global entity of food-induced hypercortisolism (Cushing’s
obesity epidemic. syndrome; see Chapter 5). In such patients, food
ingestion releases GIP from the small intestine in
4.4 Gastrointestinal Peptides: physiological concentrations. It then binds to aber-
rant adrenal GIP receptors to drive a postprandial
The Gut–Brain Axis increase in plasma cortisol. These patients develop
The neural control systems for energy homeostasis are Cushing’s syndrome due to the exuberant post-meal
dependent on accurate information from nutrient cortisol production, which is independent of ACTH
sensor mechanisms that are distributed through the (Messidoro et al., 2009). The condition is managed by
gastrointestinal (GI) tract. During and after food the removal of the adrenal gland (adrenalectomy).
ingestion, these sensors send signals to central regu- Other gut peptides, not covered here, may be
latory centers, including the hypothalamus. Such clinically useful in controlling energy intake. For
feedback signals are mediated not only by sensory example, a subcutaneous infusion of GLP-1 plus
neurons but by peptide hormones as well. This section PYY significantly reduced food intake by 32% in
will focus on several peptide hormones now known to obese volunteers (Tan et al., 2017). The combination
be important in human appetite control. of leptin and amylin is also effective in reducing body
GI tract tissue represents a large endocrine organ weight (see Figure 4.7; Ravussin et al., 2009).
that expresses at least 30 peptide genes that in turn
produce more than 100 bioactive hormonal peptides Ghrelin
(Rehfeld, 2017). These peptides target the brain to Ghrelin is primarily produced and secreted from the
control both hunger and satiety but also influence stomach. It is the most potent GH secretagogue known.
62 the GI tract directly to influence digestion, Ghrelin infusion, in men and women, synergizes with

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Figure 4.9 Meal-related changes in plasma

ghrelin. Plasma levels of (A) ghrelin and (B)
insulin during a 24-hour period in ten healthy
human subjects consuming breakfast, lunch
and dinner at the times indicated (0800, 1200
and 1730, respectively). Note the rapid
increase in ghrelin levels in the preprandial
period, falling back to control values within
1 hour after eating. Insulin surges are exactly
reciprocal. Values are means +/-SEM. Data
obtained from Cummings et al. (2001).

GHRH to stimulate pulsatile release of GH from soma- which is reversed after waking, in anticipation of
totrophs (Chapter 8; see for example Figure 8.9). breakfast (Spiegel et al., 2011).
In this section, we will outline the evidence that The determination of ghrelin levels is complicated
ghrelin is also implicated in the control of energy because the biologically active form of ghrelin is acyl
intake. Studies in experimental animals revealed ghrelin, which constitutes only about 10% of total
that plasma levels of ghrelin are increased by fast- plasma ghrelin. However, using specific immunoas-
ing and that injections of ghrelin potently increased says, a comparison of the secretory profiles of total
food intake (Gardiner et al., 2008). In human stu- ghrelin and acyl ghrelin through 24 hours indicates
dies, under physiological conditions, ghrelin levels that both are affected in the same way (Spiegel et al.,
rise and fall according to meal times, indicating 2011); that is, increases in ghrelin secretion precede
that ghrelin plays a role in the initiation of meals. meals and accompany sleep.
Figure 4.9 shows that ghrelin levels rise before Is there evidence for an effect of exogenous ghrelin
meals, followed by a rapid postprandial decline on human food intake? Infusions of ghrelin to achieve
(Cummings et al., 2001). Figure 4.9 also shows plasma levels in the physiological range in healthy
the reciprocal temporal patterns of insulin and young males failed to increase subjective hunger,
ghrelin peaks. The rise in ghrelin secretion asso- meal timing or meal size (discussed in Lippl et al.,
ciated with sleep reflects what is essentially 2012). This lack of effect is probably due to the short
a prolonged period of fasting followed by half-life of native ghrelin (30 min) and this may
a decline later during the night. This indicates a account for previous contradictory reports of
possible sleep-induced inhibition of ghrelin release, a positive effect of ghrelin on human appetite (see 63

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

e.g., Druce et al., 2005). In contrast, a synthetic, long- proglucagon polypeptide is cleaved by prohormone
acting, orally active ghrelin mimetic – anamorelin – convertases to glucagon, but in the GI tract it is
significantly increased appetite, food intake and body processed into GLP-1, which is then released from
weight in healthy volunteers (Garcia and Polvino, cells located in both the small and large intestine
2007). Based on this study, anamorelin was tested (see Figure 4.2). Secretion is rapidly stimulated by
for its effects on cancer anorexia-cachexia syndrome food intake, but GLP-1 is quickly degraded in the
(Garcia et al., 2015; Currow et al., 2017). These blood so that only approximately 15% circulates as
patients undergo involuntary weight loss with the biologically active peptide (Steinert et al., 2017).
decreased muscle mass, poor quality of life and Specific immunoassays are available to determine
decreased survival. Results indicated that 12–24 both active and inactive forms (Bak et al., 2014).
weeks of oral anamorelin treatment for patients with “Total” GLP-1 levels (active plus inactive) represent
cancer anorexia-cachexia syndrome produced the amount of GLP-1 secreted from the GI tract,
increases in lean body mass versus placebo, with whereas the “active” amounts represent the biologi-
improvements in muscle strength and quality of life cally active form necessary for the brain to respond.
(Garcia, 2017). In keeping with the studies on anor- Figure 4.10 illustrates that the pattern of meal-
exia-cachexia syndrome, levels of ghrelin are also ele- induced secretion is similar for total and intact GLP-
vated in patients with anorexia nervosa (Colldén et al., 1, although the absolute amounts are not (Carr et al.,
2017). However, as noted earlier, this conclusion is 2010; see also Alsalim et al., 2015).
uncertain because of the different forms of ghrelin These data also show that both forms of GLP-1
assayed. Nonetheless, other reports confirm elevated secretion are significantly reduced in healthy, obese
levels of ghrelin in anorexia nervosa (Hotta et al., young men compared with lean controls. This sug-
2012). Nutritional support of these patients is gests that lower levels of obesity-associated GLP-1 fail
required to improve endocrine problems and quality to reduce appetite and food intake.
of life (Schorr and Miller, 2017), but infusion of ghre- What is the evidence for GLP-1 acting as
lin over 14 days gave inconclusive results. Again, the a satiety factor to inhibit food intake in humans?
short half-life of ghrelin is a shortcoming of this Some, but not all, studies show that intravenous
investigation and the use of anamorelin would be GLP-1 given to healthy subjects significantly
justified in future studies. reduced food intake (Steinert et al., 2017).
Serum levels of ghrelin are also affected by The inconsistent results of GLP-1 treatment prob-
increases in body weight. For example, in obese chil- ably reflect the rapid degradation (elimination half-
dren – either with MC4 R or leptin gene mutations life ~2 min) of injected native GLP-1. Efforts to
(see Section 4.3) – ghrelin levels are significantly make available synthetic, long-acting GLP-1 ago-
reduced (Haqq et al., 2003) and a similar reduction nists to treat obesity have been successful. For
is seen in obese adults (BMI>30 kg/m2; Tschöp et al., example, liraglutide has a half-life of about
2001). These observations seem counterintuitive, in 13 hours and is approved for the indication of
the sense that increases in plasma ghrelin stimulate obesity (Mancini and de Melo, 2017). Figure 4.11
hunger/appetite whereas decreases are coincident illustrates the results of a double-blind, placebo-
with satiety (Figure 4.9). Since obesity is induced by controlled trial that compared the influence of orli-
increases in caloric intake, the reduction in ghrelin stat with daily, subcutaneously injected liraglutide
levels appears to be an unsuccessful attempt to sup- (Astrup et al., 2009; Pi-Sunyer et al., 2015; Halawi
press hunger. It remains possible that a ghrelin et al., 2017). Orlistat is an approved weight-loss
antagonist, by inhibiting the effects of the remaining agent that acts as a GI lipase inhibitor. Liraglutide
circulating ghrelin, could induce weight loss. induced significant weight loss at all doses com-
Research by the pharmaceutical industry is currently pared with placebo.
aimed at developing such antagonists (Davenport and Other GLP-1 agonists – such as exenatide (Byetta),
Wright, 2014). lixisenatide (Lyxumia), dulaglutide (Trulicity) and
albiglutide (Tanzeum) – are already approved in the
Glucagon-Like Peptide-1 United States and Europe for the treatment of type 2
GLP-1 is encoded by the same gene that expresses diabetes (Finan et al., 2015), and newer formulations
64 glucagon in the pancreas; that is, in the pancreas, the of exenatide and others, such as semaglutide, have

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Total GLP-1 Intact GLP-1

40 12

35

Intact GLP-1 (pmol/L)

Total GLP-1 (pmol/L)

30 8

25 Lean Lean
4
20
Obese Obese
15
0
10
0 60 120 180 240 300 0 60 120 180 240 300
Time (min) Time (min)
Figure 4.10 Effects of meal ingestion on GLP-1 in obese and lean volunteers. Subjects were given a mixed meal (560 kcals) following an
overnight fast. Plasma samples were obtained at the time intervals shown, over 300 min. Values are +/-SEM; lean volunteers (n=12) and obese
(n=13) had BMI values of 22.3 kg/m2 and 33.8 kg/m2, respectively. Data obtained from Carr et al. (2010).

–1

–2
Mean weight loss (kg)

–3
Randomization

–4 Placebo
Screening

–5
Orlistat
–6
Liraglutide 1.2 mg
–7 Liraglutide 1.8 mg
Liraglutide 2.4 mg
–8
Liraglutide 3.0 mg
–9
–5 –3 0 5 10 15 20
Weeks
Figure 4.11 Liraglutide-induced weight loss in obese individuals. These data were obtained from a double-blind, placebo-controlled trial (564
individuals; BMI=30–40 kg/m2). Four liraglutide doses were used (1.2 mg, 1.8 mg, 2.4 mg or 3.0 mg, n=90–95 per group; or placebo, n=98)
given once a day subcutaneously. Orlistat (120 mg, n=95) was given three times a day orally. The effects of liraglutide vs. placebo at week 20
were significant all doses (p=0.003 to p<0.0001). Liraglutide vs. orlistat was significant at the two highest doses (p=0.003 and p<0.0001).
Reproduced with permission (Astrup et al., 2009).

a longer half-life, making them suitable for once- promising results from early clinical tests (Tschöp
weekly injections. et al., 2016; Kleinert et al., 2017). For example,
The most frequently reported adverse events with Figure 4.12 illustrates the effectiveness of a GLP-1/
GLP-1 treatment were mild or moderate nausea and glucagon poly-agonist. The authors suggest that the
diarrhea. Efforts to circumvent these effects have coordinated action of these two hormones enhanced 65
focused on the use of drug combinations with efficacy and avoided adverse effects.
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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Target tissues

Pancreas Liver Brain SNS/BAT

Glucose handling Food intake

Insulin sensitivity Energy expenditure
Body weight
Leptin sensitivity

Figure 4.12 Effects of GLP-1/glucagon poly-agonist on obesity and type 2 diabetes. Reproduced with permission (Kleinert et al., 2017).
Abbreviations: BAT, brown adipose tissue; SNS, sympathetic nervous system.

4.4.1 A Case of Hypothalamic Obesity Fasting urine osmolality=80 mmol/kg (50–1400)

A diagnosis of hypopituitarism was made on the
A 20-year-old university student presented to the
basis of low serum cortisol and ACTH (secondary
emergency department with a 3-week history of wor-
hypoadrenalism), low serum T4 and inappropriately
sening headache and deteriorating vision. He also
normal TSH (secondary hypothyroidism), and low tes-
mentioned that during the past 3 months he had
tosterone, LH and FSH (secondary hypogonadism).
been excessively tired and noticed increased thirst
Mildly elevated serum prolactin was likely due to com-
and excessive urination. His parents indicated that
pression of the pituitary stalk (i.e., reduced dopamine
he was rapidly gaining weight (around 15 lbs in less
reaching the pituitary). A high fasting serum osmolality
than 2 months) and was always hungry. The family
with non-concentrated urine (low urine osmolality),
doctor checked his fasting serum glucose, which was
with clinical features of excessive thirst and urination,
normal at 4.8 mmol/L. Imaging studies, including
suggested diabetes insipidus (see Chapter 9). He was
computed tomography and magnetic resonance
initiated on replacement therapy with hydrocortisone,
image of the brain, showed multiple lesions including
levothyroxine, testosterone and desmopressin and was
the suprasellar area (2.1 x 2.0 cm), septum pellucidum
given combined chemotherapy (Carboplatin and
and the posterior fossa (Figure 4.13).
Etoposide) and stereotactic radiation therapy to the
A biopsy of the posterior fossa lesion confirmed
suprasellar lesion. He gained another 25 lbs over the
a germinoma. Due to the sellar involvement, he
next 3 months, at which point his weight stabilized.
underwent pituitary hormonal testing at 0900h,
Follow-up imaging studies showed regression of the
which showed the following:
suprasellar mass and stability of the remaining lesions.
Cortisol < 28 nmol/L (120–550)
He started exercising and had lost 5 lbs at his last visit.
Serum ACTH=1.1 pmol/L (2.3–10.1)
This case describes a typical scenario of hypotha-
LH<0.1 U/L (0.6–12)
lamic obesity (HO; Roth et al., 2015) which generally
FSH<0.1 U/L (1.0–12)
occurs either due to the tumor involving the hypotha-
Testosterone=8.6 nmo/L (9.0–32)
lamus, or as a result of tumor management, such as
Prolactin=42.5 mcg/L (3.5–19.4)
surgery or radiation therapy. Although craniopharyn-
TSH=1.47 mIU/L (0.35–4.3)
giomas account for almost half of these cases, germi-
Free T4=8.3 pmol/L (9.0–19)
nomas are also associated with this syndrome. HO is
GH=0.09 mcg/l (<3.0)
a complex disease caused by dysregulation of energy
Fasting serum osmolality=308 mmol/kg
66 (283–292)
metabolism and characterized by hyperphagia and

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

Figure 4.13 An MRI image (coronal section) showing the

hypothalamic lesion.

rapid, intractable weight gain. Of note, weight gain in office showed a fasting serum glucose of 6.8 mmol/L
these patients tends to continue despite caloric restric- (normal=3.6–5.7), which when repeated one week
tion (Bray and Gallagher, 1975) with significant reduc- later was 6.6 mmol/L. The referring physician was
tion in energy expenditure (Harz et al., 2003). HO is concerned that the patient had Cushing’s syndrome.
associated with a high risk of type 2 diabetes, cardiovas- The patient denied any clinical features of adrenal
cular disease, sleep apnea and non-alcoholic fatty liver or thyroid dysfunction and her periods were regular.
disease (Deepak et al., 2007). Several treatment options Her blood pressure was 140/92 mm Hg, she had gen-
have been proposed, including: severe caloric restriction, eralized obesity with no other clinical features of
sibutramine (Arango et al., 2002), amphetamines (Ismail excess cortisol (such as skin thinning, bruising, prox-
et al., 2006), metformin (Igaki et al., 2005) and GLP-1 imal muscle weakness and facial plethora) and the
analogs (Thondam et al., 2012). In addition, surgical remaining clinical exam was unremarkable.
options such as bariatric surgery have been reported Preliminary investigations revealed the following:
(Inge et al., 2007; Schultes et al., 2009). Morning serum cortisol=312 nmol/L (120–550)
TSH=2.3 mIU/L (0.35–4.3)
4.4.2 A Case of Drug-Induced Obesity Free T4=12.7 pmol/L (9.0–19)
24-hour urinary free cortisol=118 nmol/total
A 27-year-old legal secretary was referred to endocri-
volume (58–340 nmol/24 hour)
nology for abnormal glucose and weight gain despite
Serum cortisol after 48-hour low-dose dexametha-
watching her diet. Three years earlier (aged 24 years)
sone test≤28 nmol/L; suppression to < 50 is regarded
she had developed features of depression and was
as normal.
diagnosed as having bipolar disorder. Following trials
Based on an unremarkable endocrine work-up,
of several medications, she was eventually given
a preliminary diagnosis of olanzapine-induced weight
a combination of olanzapine and lithium, which sta-
gain was made. The psychiatry team was contacted,
bilized her mood. However, despite this improvement
and aripiprazole was initiated instead of olanzapine.
in mood, she rapidly gained weight and over a course
Over the next 6 months, the patient managed to lose
of 4 months gained 17 lbs and developed features of
12 lbs, her glucose and liver enzymes normalized and
sleep apnea, mild hypertension and abnormal liver
the symptoms of sleep apnea also improved.
enzymes. The latter was thought due to non-
Anti-psychotic drugs are the primary treatment
alcoholic fatty liver disease associated with weight 67
for several mental health disorders. They tend to
gain. Routine tests through her family physician’s
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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

have varied metabolic effects, with certain drugs, such general population is characterized by increased
as olanzapine and quetiapine, causing significant serum leptin from the enlarged fat mass. Obese indi-
increases in caloric intake, weight gain and a trend viduals demonstrate leptin resistance; that is, high
toward increased insulin resistance (Ballon et al., circulating levels of leptin fail to reduce food intake
2018). In contrast, the risk is relatively low with ari- or body weight. Thus, leptin cannot be used to ther-
piprazole. The neural mechanisms underlying human apeutically reduce body weight.
weight gain after anti-psychotic drug treatment are Mutations in the leptin–melanocortin signaling
not fully understood. Several mechanisms have been pathway also induce obesity and hyperphagia.
proposed for the effects of olanzapine, including their Patients with a POMC gene mutation have early-
effect on serotonin, dopamine and histamine recep- onset obesity and severe hyperphagia. They lack α-
tors as well as an effect of these drugs on leptin (Ak MSH that normally stimulates MC4 R receptors.
et al., 2013), adiponectin and ghrelin (Hosojima et al., Patients with this type of mutation respond to
2006; Lu et al., 2015; for review see Henderson et al., MC4 R agonists, such as setmelanotide, with signifi-
2015). Switching therapy to an agent with lower risk cant loss of body weight and reductions in hunger
of weight gain as well as dietary counseling and life- scores.
style changes are generally used as the primary treat- The most common syndromic obesity disorder is
ment for these patients. PWS, although it remains unknown whether the cri-
tical leptin–melanocortin pathway is solely responsi-
4.5 Chapter Summary ble for the obesity. PWS occurs through a lack of
This chapter focuses on how hypothalamic neuroen- multiple paternally inherited genes on chromosome
docrine pathways regulate human appetite and body 15q11.2-q13 and the accompanying hypothalamic
weight, with emphasis on their role in the pathogen- dysfunction results in obesity/hyperphagia, faulty
esis of obesity. Obesity is strongly associated with an temperature control, high pain threshold, hypersom-
escalating incidence of cardiovascular disease, type 2 nia and multiple endocrine abnormalities. A contem-
diabetes, osteoarthritis, certain cancers, hypertension, porary approach to identifying genes implicated in
stroke and Alzheimer’s disease. The major neural the pathogenesis of obesity is possible because of the
centers for the regulation of appetite are located in sequencing of the human genome. A new gene
the hypothalamus, which integrates long-term signals robustly linked to human obesity is the FTO gene.
(e.g., leptin) from adipose tissue, and short-term The GI tract is a large endocrine organ expressing
meal-related signals (e.g., gut-derived hormones many peptide genes. These peptides target the brain to
such as ghrelin) to regulate food intake. This regula- control both hunger and satiety. For example, ghrelin
tory system is called the leptin–melanocortin path- (from the stomach) is orexigenic; GLP-1 and PYY
way, a neuronal complex that includes leptin (from the small intestine), CCK (from the duodenum)
receptors, POMC neurons and receptors for various and amylin (from the pancreas) inhibit appetite and
gut hormones such as ghrelin and GLP-1. are therefore anorexigenic. They represent variable
Adipose tissue is an endocrine organ that secretes short-term signals triggered by eating patterns, in
adipokine hormones, of which leptin is the archetypal contrast to leptin that exerts a long-term regulation
member. The vital importance of leptin is revealed in that reflects adipose tissue stores.
humans carrying leptin gene mutations that reduce Ghrelin levels rise before meals, followed by a rapid
leptin levels. These individuals are severely obese and postprandial decline, suggesting that ghrelin plays
exhibit intense hyperphagia, but respond to recombi- a role in the initiation of meals. However, infusions
nant human leptin with a remarkable reduction in fat of ghrelin in healthy young males failed to increase
levels and body weight. Other forms of leptin defi- hunger or meal size. This lack of effect is probably due
ciency, such as exercise-induced amenorrhea, are also to ghrelin’s short half-life (30 min). In contrast, a long-
treatable with leptin to restore fertility. acting, orally active ghrelin mimetic – anamorelin –
Lipodystrophy – the complete or partial absence of significantly increased appetite, food intake and body
fat tissue – also produces leptin deficiency, severe weight in healthy volunteers. When tested for an effect
insulin resistance and hyperphagia. Replacement in anorexia-cachexia syndrome patients, anamorelin
doses of leptin induce improvements in insulin sensi- increased lean body mass, with improvements in mus-
68 tivity and glucose tolerance. In contrast, obesity in the cle strength and quality of life.

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

In contrast to ghrelin, GLP-1 secretion is rapidly d. Intravenous GLP-1 infusion readily reduces
stimulated by food intake. That GLP-1 acts as a satiety food intake in humans.
factor to inhibit food intake in humans is demon- e. Liraglutide injection effectively reduces food
strated by the ability of a long-acting agonist – liraglu- intake.
tide – to induce significant weight loss at all doses 6. Which of the following are associated with
compared with placebo. Prader–Willi syndrome?
Two cases of obesity are included.
a. Hypothalamic dysfunction
b. Cryptorchidism
4.6 Review Questions c. Tall stature
1. Which gastrointestinal (GI) tract hormone d. Hyperphagia
stimulates appetite when the stomach is empty? e. Hypogonadism
a. Amylin 7. Which of the following statements are correct with
b. Leptin respect to GLP-1 analogs?
c. Cholecystokinin a. Can cause food-induced Cushing’s syndrome
d. Ghrelin b. Nausea is associated with GLP-1 therapy
e. Glucagon-like peptide-1 (GLP-1) c. Are recommended for management of
2. Which of the following are associated with obesity diabetes
and hyperphagia in children? d. Some patients may experience significant
weight loss with GLP-1 analog therapy
a. Mutations in the leptin receptor
e. Require multiple daily injections due to short
b. Mutations in the melanocortin receptor gene
half-life
c. Absent circulating leptin
d. Elevated biologically inactive leptin 8. Which of the following conditions can lead to
e. All of the above significant weight gain?
3. Exercise-induced amenorrhea (hypothalamic a. Poorly controlled diabetes
amenorrhea) is characterized by which of the b. Hyperthyroidism
following? c. Hypothalamic injury
d. Addison’s disease
a. High, pulsatile secretion of luteinizing
e. Drug-induced hyperprolactinemia
hormone (LH)
b. Low levels of circulating leptin 9. Which of the following statements regarding
c. Low levels of estradiol leptin and type 2 diabetes are correct?
d. Subnormal levels of LH a. Most adult patients with type 2 diabetes are
e. High body mass index leptin deficient.
4. Mutations in the leptin gene cause gross obesity in b. Leptin therapy in obese type 2 diabetes
children and in adults. Leptin treatment induces patients is associated with significant weight
weight loss in such patients. Why is leptin loss.
ineffective in reducing body weight in diet-induced c. Obese type 2 diabetes patients may develop
obesity? Which GI tract peptide has proven useful resistance to endogenous leptin.
in synergizing with leptin to reduce body weight? d. Leptin deficiency in children can lead to type 2
5. GLP-1 is an anorexigenic peptide released from diabetes.
the GI tract after food ingestion. Which of the e. Leptin deficiency in patients with
following statements are correct? lipodystrophy may lead to diabetes.
a. GLP-1 levels are increased in obese individuals 10. Which of the following are correct with regard to
compared to lean subjects. hypothalamic obesity (HO)?
b. GLP-1 levels increase coincident with insulin a. HO is characterized by rapid weight gain.
secretion. b. Weight gain in HO can be effectively treated
c. GLP-1 is rapidly degraded following food with caloric restriction.
ingestion. c. Hyperphagia is a characteristic feature of HO. 69

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 Chapter 4: Neuroendocrine Regulation of Appetite and Body Weight

d. Craniopharyngiomas are the commonest Angulo M A, Butler M G & Cataletto M E. (2015). Prader-
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Cataletto M, Angulo M, Hertz G & Whitman B. (2011). Bak M J, Albrechtsen N J W, Pedersen J et al. (2014).
Prader-Willi syndrome: a primer for clinicians. Int J Ped Specificity and sensitivity of commercially available assays
Endocr 2011, 12. for glucagon-like peptide-1 (GLP-1): implications for
Chakradhar S. (2016). All in one: researchers create GLP-1 measurements in clinical studies. Diabetes Obes
combination drugs for diabetes and obesity. Nat Med 22, Metab 16, 1155–1164.
694–696. Bakker N E, Wolffenbuttel K P, Looijenga L H & Hokken-
Flier J S & Maratos-Flier E. (2017). Leptin’s physiologic role: Koelega A C. (2015). Testes in infants with Prader-Willi
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Friedman J. (2016). The long road to leptin. J Clin Invest Bakker N E, Lindberg A, Heissler J et al. (2017). Growth
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