Review

Special issue: neural control of appetite

Mechanisms underlying current

and future anti-obesity drugs
Roger A.H. Adan
Rudolf Magnus Institute, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands

Regulation of body weight is organized by distributed

brain circuits that use a variety of neuropeptides and
transmitters, and that are responsive to endocrine and
metabolic signals. Targeting of these circuits with novel
pharmaceutical drugs would be helpful additions to
lifestyle interventions for the treatment of obesity.
The recent FDA approval of two anti-obesity drugs holds
promise in a field in which previous drugs were removed
from clinical use because of unacceptable psychiatric
and cardiovascular side effects. Here, the modes of
action of anti-obesity drugs are reviewed.
What to target to treat obesity?
A successful weight-loss drug should reduce energy intake
and/or increase energy expenditure without adverse side
effects. Which aspect of energy balance could best be targeted by drugs? Most energy expenditure is due to the basal
metabolic rate (BMR) [1]. Drugs that target the BMR, such
as dinitrophenol and thyroid hormone, successfully reduce
body weight but are associated with serious side effects (Box
1, Table 1). Energy expenditure does not fluctuate extensively during the day, except when performing physical
exercise. By contrast, energy intake is highly variable during the day (Box 2). Thus, drugs that target energy intake,
such as phentermine and sibutramine, act on the more
dynamic part of the energy balance equation. Initiation of
energy intake is triggered by habits (e.g., eating three times
a day), by different types of internal and external cues that
trigger (palatable) food intake, and by social pressure (e.g.,
to participate in the consumption of a snack or a high-calorie
drink). The amount ingested depends on the portion size
available, satiation (see Glossary), and cognitive restraint
(the ability to terminate intake without being satiated).
Differences in the number and size of meals and snacks
and the choice of food strongly affect the variability between
individuals in energy intake. Drugs that delay initiation of
meals or snacks (affecting hunger), reduce portion size
(affecting satiation signaling), or affect the choice of food
would potentially be effective in reducing energy intake and
consequently body weight.
In the brain, the initiation, termination, and choice of
meals is controlled by distinct and interconnected neural
circuits that use a variety of neurotransmitters and neuropeptides and that receive input on the status of energy
balance via endocrine factors and peripheral nerves
(Figure 1) [2,3]. The specificity of these signals provides
Corresponding author: Adan, R.A.H. (r.a.h.adan@umcutrecht.nl).
Keywords: satiety; monoamines; weight loss drug.

great potential for the development of weight loss drugs.

Most anti-obesity drugs in the past, such as sibutramine
and amphetamines, targeted monoaminergic systems (often originating from the development of psychotropic
drugs). How monoamines such as dopamine, serotonin,
and noradrenalin are involved in affecting energy balance
is only partly understood. This is still an important issue to
address, because the anti-obesity drugs lorcaserin and
Qsymia recently approved by the FDA, as well as upcoming
drugs such as tesofensine and Contrave, target monoaminergic systems (Table 1). Novel anti-obesity drugs targeting other signaling molecule classes that are based on
insights into the regulation of energy balance in particular food intake are also currently being developed [1,49].
In this review, I focus on describing how anti-obesity drugs
act on the nervous system to reduce body weight.
Targeting distinct circuits in the brain
Serotoninergic system
Serotonin is involved in satiety and satiation [2,3,911] via
at least three different types of neurons expressing different serotonin receptors. First, serotonergic drugs, such as
meta-chlorophenylpiperazine (mCPP), have anorectic
effects via activation of serotonin 2c (5-HT2C) receptors
on pro-opiomelanocortin (POMC) neurons [12]. Arcuate
POMC neurons are primary targets for leptin and other
peripheral hormones and increase their activity after
meals and during positive energy balance. An increase
in the firing rate of POMC neurons results in release of
melanocortins (MCs) and b-endorphin at POMC neuronal
projections. Activation of MC4 receptors in secondary neurons is implicated in mediation of the effect of serotonin on
POMC neurons [13]. The MC4 receptor is itself an attractive obesity drug target because common genetic variants
close to the MC4 receptor explain some of the difference in
body mass index (BMI) between individuals [14], and MC4
Glossary
Anorectic: food intake-reducing.
Indirect agonist: ligand that enhances the release or activity of an endogenous
agonist by, for instance, acting on a transmitter transporter or an enzyme that
breaks down an endogenous agonist with the result that the concentration of
the endogenous agonist near the receptor remains high.
Inverse agonist: ligand that binds to a receptor and not only hinders the
binding of an agonist (thus acting as an antagonist) but also reduces the
spontaneous receptor activity that occurs in the absence of agonist.
Satiation: process that leads to termination of an ongoing meal.
Satiety: process that results in postponing initiation of the next meal.
Sympaticomimetic: drug that mimics the action of noradrenalin.
Post-prandial: after a meal.

0166-2236/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2012.12.001 Trends in Neurosciences, February 2013, Vol. 36, No. 2

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Box 1. History of obesity drugs

In the 19th century, preparations containing thyroid hormone were
used as anti-obesity drugs (Figure I) [5]. Thyroid hormone increases
the BMR and thus increases energy expenditure. Side effects include
symptoms of hyperthyroidism, such as restlessness and sleep
problems, as well as increased risk of heart failure [4]. Another drug
that increases energy expenditure, dinitrophenol, was used to lose
weight a century ago. It uncouples oxidative phosphorylation from
the generation of ATP in mitochondria, so that heat rather than ATP is
generated. It was a successful weight loss drug, but overheating was
a risk, which resulted in deaths [4,5]. Both treatments demonstrate the
efficacy of drugs to lose weight by increasing BMR.
Amphetamines are sympaticomimetics that reduce feeding and
increase locomotor activity. Amphetamines have been successfully
used as weight-loss drugs since the 1930s, but were abandoned
because of their cardiovascular side effects and addictive properties,
although phentermine is still prescribed for the first weeks during
weight loss programs [89]. As a monotherapy, phentermine is one of
the safer amphetamines and results in bodyweight loss of 34 kg more
than for placebo after 3-month treatment [90]. Phentermine was
combined with fenfluramine in FenPhen, a popular weight-loss drug
20 years ago with efficacy of up to 10% bodyweight loss [5,91]. This
successful drug was abandoned because it often induced pulmonary
hypertension [92]. Sibutramine, a noradrenalin and serotonin reuptake
inhibitor, was introduced in the late 1990s as a weight-loss drug [93,94].
Although on average it leads to bodyweight loss of 45 kg over 1 year
[90], it was withdrawn in 2010 because of cardiovascular side effects,
which resulted in increased heart attacks and strokes [5]. Rimonabant,
an antagonist at the CB1 receptor, was approved by the European
Medicines Agency (EMA) and introduced in Europe in 2006. It resulted
in 4.55 kg more weight loss than for placebo after 1-year treatment [95]
but was withdrawn in 2008 because it was associated with increased
anxiety and depressive symptoms. Orlistat is currently the only widely
available drug for treating obesity. It results in bodyweight loss of
23 kg on average following 1 year of treatment [90]. It is a gastric and
pancreatic lipase inhibitor approved in 1998 [95]. Currently it is the most
widely prescribed anti-obesity drug. It has poor compliance because of
its side effects (e.g., fecal incontinence, oily stools).
Qsymia and lorcaserin are novel additions to the limited repertoire
of anti-obesity drugs. Lorcaserin results in 34% more body weight

receptor mutations cause obesity in mice and humans [15].

Reduced MC receptor signaling in the dorsal vagal complex
(DVC), paraventricular nucleus (PVN), lateral hypothalamus, and ventromedial hypothalamus (VMH) increase
meal size and body weight [16,17]. A clinical trial in which
the efficacy of a selective MC4 receptor agonist (MK 0493)
was tested showed modest weight reduction [18]. Besides
their effect on reducing appetite, MC agonist drugs stimulate the sympathetic system, resulting in increased blood
pressure, which is an unwanted side effect for an antiobesity drug [19].
Second, the satiating effects of serotonin are mediated
via 5-HT1b receptors expressed on arcuate neuropeptide Y
(NPY)/Agouti-related protein (AgRP) neurons. NPY and
AgRP are orexigenic neuropeptides that act as agonists on
NPY receptors and inverse agonists at MC receptors (i.e.,
they antagonize MCs), respectively. Both NPY receptor
subtypes Y1 (NPY1R) and Y5 (NPYR5) are implicated in
the orexigenic effects of NPY [20]. MK-0557, a potent and
highly selective orally active NPY5R antagonist, modestly
reduced body weight in humans [21]. GABA may be the
more important transmitter in these NPY/AgRP neurons
that project to multiple nuclei implicated in food intake.
Via 5-HT1b receptors, serotonin hyperpolarizes these neurons. One projection site is onto arcuate POMC neurons,
134

loss compared to placebo after 1 year of treatment [28,29]. Whereas

topiramate as monotherapy results in 67% more bodyweight loss
compared to placebo [96] when it is combined with phentermine (in
Qsymia), it has an efficacy of 910% more bodyweight loss compared
to placebo after 1 year of treatment [29]. Bupropion results in 23 kg
of bodyweight loss [90] and when combined with naltrexone (as in
Contrave) results in 45% more bodyweight loss compared to placebo
after 1 year of treatment [29,51,97]. Nausea is the most common side
effect [97].

Before 1900

Thyroid hormone preparaons

used to lose weight

Dinitrophenol causes weightloss by generang heat

1920s
1930s

First amphetamines introduced

FDA approval of phentermine

as appete suppressant
1959

1992
O-label use of combinaon
of fenuramine and
phentermine (Fen-Phen)

FDA approval of sibutramine

1997
1999

FDA approval of orlistat

EMA approval of rimonabant

2006
2012

FDA approval of lorcaserin

and QsymiaTM
TRENDS in Neurosciences

Figure I. Timeline indicating some of the main classes of anti-obesity drugs that
have been introduced into the market.

which are then disinhibited [9]. Another projection is to the

PVN. Optogenetic stimulation of arcuate NPY/AgRP
GABAergic neurons projecting to the PVN demonstrated
the importance of this connection for food intake [22] and a
decrease in the activity of these neurons by serotonin
would reduce food intake.
Third, serotonergic neurons in the brain stem (i.e., in the
raphe obscurus and raphe magnus, which are part of the
medial raphe nucleus) also affect food intake. These serotonergic neurons project to the nucleus of the tractus solitarius
(NTS) and synapse onto 5-HT3-receptor-expressing glutamatergic neurons. These subsequently project to the parabrachial nucleus (PBN) [23]. Activation of PBN neurons is
associated with conditioned taste aversion and reduced food
intake [24]. Serotonin decreases the activity of NTS glutamatergic neurons projecting to the PBN, and thus reduces
food intake. In addition, activation of 5-HT1b inhibits the
activity of arcuate NPY/AgRP GABAergic neurons projecting to the PBN and this may further contribute to the
anorectic effects of increased serotonergic tone [25].
Increasing serotonergic activity has been a successful
approach in combating obesity. Fenfluramine (Box 1)
enhances serotonin release by acting on the vesicular
monoamine transporter (VMAT2) and as a selective
serotonin reuptake inhibitor (SSRI). It reduces appetite

Review

Trends in Neurosciences February 2013, Vol. 36, No. 2

Table 1. Mechanisms of action of anti-obesity drugs

Drug
Contrave
(bupropion with naltrexone)
Empatic
(bupropion with zonisamide)
Fen-Phen
(fenfluramine/phentermine)
Lorcaserin

Main mechanism of action

Noradrenalin/dopamine reuptake
inhibitor and opioid receptor antagonist
Noradrenalin/dopamine reuptake
inhibitor and anti-convulsant
Serotonin/noradrenalin releasers

Introducedwithdrawn
Declined in 2011; may be
refiled
Phase II testing

Orlistat
Phentermine

Gastric and pancreatic lipase inhibitor

Noradrenalin releaser, sympaticomimetic

Qsymia
(phentermine with topiramate)
Rimonabant

Noradrenalin releaser and anti-convulsant

Sibutramine

Serotonin/noradrenalin reuptake inhibitor

Tesofensine

Serotonin/noradrenalin/dopamine reuptake
inhibitor

19921997
(only in USA)
2012present
(only in USA)
1999present
1959present
(only in USA)
2012present
(only in USA)
20062008
(only in Europe)
19972010

Serotonin 2C agonist

CB1 receptor antagonist

Side effects
Cardiovascular side effects
Nausea, headache, insomnia,
anxiety
Valvular heart disease, pulmonary
hypertension
Dizziness, headache, insomnia
Fatty and oily stools
Only for short term use in
patients without hypertension
Dizziness, headache, insomnia
Depression and anxiety
Increased risk for stroke
and myocardial infarction
Depressed mood, possibly
cardiovascular side effects

Phase III testing

Box 2. Fluctuations in energy balance during 24 h

Energy balance fluctuates strongly during the day (Figure I). In
particular, during feeding there are sharp increases in energy present
in the body. Energy loss by expenditure is more gradual. The BMR is
23.51.9 kcal/kg for normal-weight men and 22.52.1 kcal/kg for
women [1], which translates to approximately 1760 kcal for a 75-kg
man and 1570 kcal for a 70-kg woman. BMR results in regular
decreases in energy stores, even during sleep. An office worker uses
300 kcal/day of energy on top of BMR, whereas a farmer may expend

2000 kcal/day extra on physical activity [98]. There is a stronger

decrease in energy stores with exercise (such as cycling to work).
Eating rapidly increases the amount of energy in the body. A
McDonalds Happy Meal ranges from 380 to 700 kcal, depending on
the ingredients chosen. A glass of soft drink or wine is approximately
100 kcal, a small bag of crisps 60200 kcal, and a minibar snack
approximately 40 kcal. Thus, a couple of snacks and soft drinks easily
have the same amount of calories as a meal.

1000

Intake

Expenditure

400
200

Time of day
5 a.m.

1 a.m.

9p.m.

Cycling

Daily acvity
Cycling

-400

5 p.m.

-200

1 p.m.

9 a.m.

Energy balance (kCal)

A drink
A snack

Dinner

Lunch

600

Key:
Breakfast

800

Sleep

TRENDS in Neurosciences

Figure I. Energy balance during a typical workday. Fluctuations in energy balance (with energy rising during feeding and decreasing on expenditure) during a workday
for a man who spends most of his work at a desk, cycles to work, and eats three meals plus drinks and snacks during the day and in the evening. Colors in the figure on
the left correspond to those in the bar graph on the right and indicate the relative amounts of energy taken in or spent.

and body weight. Interference with VMAT2 function may

be essential for the effect of fenfluramine in reducing body
weight, because more selective serotonin reuptake inhibitors (e.g., paroxetine) have a tendency to increase body
weight [26].
The downside of serotonergic indirect agonist drugs
such as fenfluramine and sibutramine is that they also
activate 5-HT2b receptors. Activation of 5-HT2b receptors is
associated with heart valvulopathy [27]. The 5-HT2c receptor is expressed in the brain but not in the heart. Therefore,
side effects such as valvulopathy are not expected for

selective 5-HT2c agonists. Lorcaserin is a selective 5HT2c agonist that has been successful in reducing body
weight [28]. The efficacy of lorcaserin in reducing weight
may be somewhat less than the indirect serotonin agonists,
which also target the other 5-HT receptor subtypes that
have been implicated in reducing food intake [29].
Noradrenergic system
Increased noradrenalin signaling results in weight
loss. Noradrenalin is the principal transmitter in postganglionergic sympathetic neurons and drugs mimicking
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Trends in Neurosciences February 2013, Vol. 36, No. 2

Stria

tum

HT1B D2
D1
HT2C

D2
SN CB1
VTA
2
1
PVN
CB1
DMH

D2 CB1
VMH

NTS DVC
HT3
PBN
AP

LH
5HT 2
1

CB1

NOR

Amylin
PP

Arcuate

POMC

NPY

CB1 AgRP HT1B

HT2C

Lepn
Ghrelin
Glp-1
PYY3-36
TRENDS in Neurosciences

Figure 1. Simplified feeding neural circuitry. Hindbrain neural circuits (within the orange circle), including the dorsal motor nucleus of the vagus complex (DVC), the
nucleus of the tractus solitarius (NTS), area postrema (AP), and parabrachial nucleus (PBN), control satiation. Amylin and pancreatic polypeptide (PP) affect satiation via
their activity on the brain stem. Rostral brain areas modulate satiation via their projections on NTS and DVC [99]. In a satiated state, initiation of (palatable) food intake is
elicited by injection of opioids in the ventral striatum [100] or by electrical stimulation of the lateral hypothalamus (LH) [101]. Green arrows indicate projections that
stimulate feeding when activated. Red arrows indicate projections that inhibit feeding. Pro-opiomelanocortin (POMC) and neuropeptide Y (NPY)/Agouti-related protein
(AgRP) neurons originate in the arcuate nucleus. Leptin, ghrelin, glucagon-like peptide 1 (Glp-1) and peptide YY336 (PYY336) act on these and other neurons. Serotonin
(5HT) and noradrenalin (NOR) neurons originate in the brain stem. The mesolimbic dopamine system is shown in purple with some of its connections. Receptors are
depicted in black. The hypothalamus is in green. The blue arrow indicates the mesolimbic dopamine projection. Abbreviations: D1, dopamine 1 receptor; D2, dopamine 2
receptor; HT1B, serotonin 1B receptor; HT2C, serotonin 2C receptor; HT3, serotonin 3 receptor; a1, a1 adrenoceptor; b2, b2 adrenoceptor; CB1, cannabinoid 1 receptor; m,
mu opioid receptor; k, kappa opioid receptor; d, delta opioid receptor.

noradrenalin are sympaticomimetics. Noradrenergic neurons in the brain stem project ventrally to the lateral (and
medial) hypothalamus [30]. Lesioning of this pathway
results in obesity and attenuates the anorectic effect of
amphetamine. Dorsal projections from these noradrenergic
nuclei innervate rostral parts of the brain, but en route send
fibers to the hypothalamus. Lesioning of this projection
results in weight loss [30]. This suggests that the ventral
pathway is more important for the anorectic effects of
sympaticomimetics. Activation of a1- and b2-adrenoceptors
decreases food intake [30]. a1-Adrenoceptors within the
PVN are excitatory and may function to suppress food
intake [30]. Thus, one site where sympaticomimetics reduce
food intake is via PVN a1-adrenoceptors. The identity of
these PVN neurons is unknown, but neurons releasing
thyrotrope- or corticotrope-releasing hormones, as well as
oxytocin neurons in the PVN, have been implicated in
reducing food intake [31].
Noradrenergic neurons in the brain stem also innervate
serotonergic neurons. Serotonergic neurons in the medial
raphe nucleus are stimulated by a1-adrenoceptor agonists
[32] and noradrenalin may mediate some of its anorectic
effects via this pathway. Thus, increased noradrenergic
signaling in these brain stem serotonergic neurons may
contribute to the satiating effects of sympaticomimetics.
Postganglionic sympathetic neurons release noradrenalin in target organs. Via this route, lipolysis in adipose
tissue is stimulated mainly via activation of b3-adrenoceptors, which are selectively expressed on adipocytes [33].
136

Some of the weight-reducing effects of amphetamines may

be mediated via this pathway. b3-Adrenoceptor agonists
have been considered as weight loss drugs but it has not
been shown that they significantly affect body weight
[34,35]. Although an increased metabolic rate is observed
in the first weeks of clinical treatment with b3 agonists,
this effect was not sustained in the long term [36].
Phentermine increases the release of noradrenalin and is
the only amphetamine-like drug that is currently available.
It is only available for short-term use (<12 weeks) to avoid
dependence on the drug because of its addictive properties
and to avoid cardiovascular toxicity, because it increases
blood pressure and heart rate [5]. It is also one of the two
constituents in the anti-obesity drugs Qsymia and FenPhen, and new formulations are being evaluated [37].
Dopaminergic system
Eating induces dopamine release in the striatum, which is
correlated with the pleasantness of a meal [38]. Stimulation with dopamine D1 receptor agonists in the striatum
increases palatable food intake, whereas stimulation of D2
receptors results in a reduction in intake [39]. Dopamine
differentially affects striatal neuronal activity. D1 receptor
activation is stimulatory for one subset of striatal medium
spiny neurons (MSNs, which are part of the direct dopaminergic pathway), whereas D2 receptors are inhibitory
and expressed on the other class of MSNs (forming part of
the indirect dopamine pathway). The balance in activity
between these two sets of striatal neuronal populations

Review
perhaps affects susceptibility to weight gain, because
reduced expression of the D2 receptors increases compulsive-like food-seeking in rats [40] and obese humans
have decreased D2 receptor binding in the striatum [41].
There is a discrepancy between the acute effects of dopamine during feeding and food anticipatory activity and
results from long-term interference in dopamine signaling.
Treatment with D2 antagonists results in body weight
gain, suggesting that stimulation of D2 receptors suppresses food intake over the long term [42]. However,
dopamine-deficient mice fail to eat, and restoration of
dopamine signaling in the dorsal striatum restored feeding
in these mice [42]. These findings suggest that dopamine is
essential for feeding, but that too much dopamine reduces
food intake. At the level of the hypothalamus, dopamine
reduces food intake via the ventromedial and lateral
hypothalamus and via increasing POMC expression in
the arcuate nucleus [43]. In addition, within the hypothalamus there is a small subset of dopaminergic neurons
(catecholaminergic cell groups A12A15) for which a role
in energy balance is unknown.
Monoamines interact with one another, which complicates elucidation of the effect of one monoamine from
another. One type of monoaminergic receptor may be
presynaptically expressed on terminals that release vesicles containing another monoamine. Serotonin, for instance, exerts an inhibitory effect on dopamine signaling
via 5-HT1b and 5-HT2c receptors in the mesolimbic and
nigrostriatal pathway [44,45], which adds to the complexity with which these neurotransmitters affect feeding.
Monoamine reuptake inhibitors remain an interesting
class of anti-obesity drugs. Reuptake inhibition of dopamine without inhibition of VMAT2, such as with vanoxerine, results in an anorectic effect [46], suggesting that
dopamine reuptake inhibition is sufficient to reduce food
intake. In addition, increased dopamine signaling results
in greater locomotor activity, which contributes to weight
loss by increasing energy expenditure. Bupropion, a noradrenalin and dopamine reuptake inhibitor, is another
promising weight-loss drug. Bupropion increases the excitability of arcuate POMC neurons [47]. Inhibition of
dopamine and noradrenalin by bupropion results in more
body weight loss compared to reuptake inhibitors targeting only one of these transmitters [48,49]. Tesofensine is a
noradrenalin/dopamine/serotonin reuptake inhibitor that
is currently being evaluated as a weight loss drug. It was
originally developed as an antidepressant, but in (pre)clinical studies its effect on weight loss was noted. The
highest dose of tesofensin tested resulted in 10% weight
loss compared to 2% in a dietary control group over 6
months [50].
Combining two drugs in one pill
Rather than combining different activities in one molecule, such as in tesofensin, novel anti-obesity drugs are
often combinations of active molecules. Contrave is such
an anti-obesity drug and consists of bupropion and naltrexone [51]. It combines a noradrenalin/dopamine reuptake inhibitor with a m/k opioid receptor antagonist.
Opioid receptor agonists, such as morphine and synthetic
enkephalin analogs, increase food consumption, whereas

Trends in Neurosciences February 2013, Vol. 36, No. 2

opioid antagonists reduce appetite [52]. Opioid receptors

are expressed widely in the brain, including neural circuits related to energy balance [53]. In the hypothalamus,
k-opioid receptors (KORs) are expressed on AgRP neurons
and m-opioid receptors (MORs) on POMC neurons. MORs
on POMC cells are thought to be inhibitory autoreceptors,
because POMC neurons release b-endorphin, an agonist
for MORs. Opioid antagonists increase the firing of POMC
neurons via MOR blockage and hence act to interrupt this
negative feedback loop [54]. In the reward circuit, MORs,
KORs, and d-opioid receptors (DORs) are expressed in the
ventral tegmental area (VTA), as well as in the nucleus
accumbens. MOR activation in the ventral striatum
increases fat intake [55]. Opioid antagonism reduced palatable food intake, which is associated with a reduction in
dopamine release in the ventral striatum [56]. KORs are
expressed in the PVN and MORs in the lateral hypothalamus, whereas the VMH expresses all three opioid receptors. It is not clear to what extent these sites contribute to
the efficacy of opioid antagonists in decreasing appetite.
Another novel combination found in anti-obesity drugs
is with antiepileptic drugs such as topiramate and zonisamide, which induce weight loss as a side effect [57,58].
The FDA approved Qsymia, which is a combination of
phentermine and a slow-release formulation of topiramate.
The doses of these drugs were chosen such that they still
reduce body weight but without too many adverse side
effects [59,60]. In Empatic, bupropion is combined with
zonisamide [59]. One of the modes of action of antiepileptic
drugs is to increase GABAergic and reduce glutamatergic
AMPA receptor signaling. In humans, the GABA agonist
baclofen has a modest weight-loss effect [61], suggesting
that an increase in GABAergic tone has a weight-suppressing effect. GABA, the main inhibitory neurotransmitter,
has an ambivalent role in feeding. It is a ubiquitous
neurotransmitter, so it is difficult to assess where in the
brain enhanced GABAergic signaling acts to reduce appetite. In mice, genetic deletion of the vesicular GABA transporter (VGAT) from neurons results in a deficiency in
GABA release. Selective deletion of VGAT from neurons
that express the leptin receptor results in obesity [62],
whereas deletion of VGAT from NPY/AgRP neurons
results in a lean phenotype [3]. One mode of action of
topiramate and zonisamide may thus be that they enhance
the efficacy of GABA released from leptin-responsive neurons. Both drugs also have other actions, such as inhibition
of carbonic anhydrase V [63], voltage-gated sodium channels, and voltage-gated calcium (T-type) channels [64],
which may have effects on energy balance via central or
peripheral pathways.
Endocannabinoid system
Cannabis and other cannabinoid (CB) receptor agonists
increase feeding and body weight [65]. By contrast, mice
lacking CB1 receptors are lean [66] and suppression of
endocannabinoid signaling in the hypothalamus has been
associated with the anorectic effects of leptin [67]. CB1
receptors are widely expressed in the brain, including the
PVN, VMH and arcuate nucleus, as well as in the VTA and
amygdala [68]. The weight loss effects of CB1 receptor
antagonists, such as rimonabant, are probably because
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Review
of antagonism of endocannabinoids at the level of the
hypothalamus, although peripheral antagonism also
appears to contribute significantly [69]. CB1 receptor
antagonists, for instance, also inhibit lipolysis in adipocytes [70]. Rimonabant was taken off the market because it
was associated with depression and suicidal thoughts [71].
Recent insights into the mode of action of CB1 receptors
may revive interest in this receptor as an anti-obesity
target. Peripheral inverse agonists (i.e., those that are
not able to cross the bloodbrain barrier) devoid of anxiogenic effects reduced obesity in a diet-induced obesity
mouse model [72]. In addition, neutral antagonists of
the CB1 receptor were as effective as the inverse agonist
rimonabant in reducing body weight in rats, but without
inducing anxiety or depression-associated behaviors [73].
Thus, the depression- and anxiogenic-inducing properties
of rimonabant may be caused by inverse agonism that
reduced the constitutive activity of CB1 receptors in the
VTA and amygdala, whereas its weight loss effects are due
to antagonism of endocannabinoids at CB1 receptors within the hypothalamus [73]. However, in the periphery,
inverse agonism rather than neutral antagonism at CB1
receptors may contribute to weight loss [72]. These findings
open avenues for the development of drugs that target the
CB1 receptor.
Targeting hunger and satiety signaling to the brain
Days after gastric bypass surgery (in particular Roux-en-Y
gastric bypass), appetite is reduced and this is associated
with lower ghrelin levels and increased levels of peptide YY
(PYY) and glucagon-like peptide-1 (GLP-1) [74]. These
hormonal changes may contribute to the efficacy of gastric
bypass and have increased the interest to mimic these
changes pharmacologically in order to treat obesity.
Plasma ghrelin levels correlate with hunger scores [75].
Ghrelin release is increased following dieting [76] and
remains elevated even after 1 year of weight loss [77].
Ghrelin may thus contribute to relapse to increased food
intake and weight gain after dieting. Ghrelin receptor
antagonists may help to decrease feelings of hunger while
dieting; however, these drugs have not reached clinical
testing yet [78]. Active ghrelin is n-octanoylated, a reaction
catalyzed by ghrelin-O-acyl transferase (GOAT) [79].
GOAT antagonists may therefore be applicable as weight
loss drugs [80].
GLP-1 is released post-prandially, retards gastric emptying, and mediates satiety. Long-acting GLP-1 agonists
(e.g., exenatide and liraglutide) enhance insulin release
and have been developed for the treatment of type 2
diabetes. These GLP-1 agonists result in body weight loss
[81]. Daily injections of liraglutide for 1 year resulted in
5.8 kg more bodyweight loss than for placebo [82]. GLP-1 is
inactivated by dipeptidyl peptidase-4 (DPP-4), and thus
DPP-4 inhibitors indirectly result in increased GLP-1
levels and reduced body weight [83].
PYY is a satiety hormone that is processed by DPP-4 to
PYY336. Infusion of PYY336 in humans decreased 24-h
caloric intake [84], despite controversy regarding its
satiating effect among species [85]. PYY336 is an agonist
for Y2 receptors. Y2 receptors expressed on AgRP/NPY
138

Trends in Neurosciences February 2013, Vol. 36, No. 2

arcuate nucleus neurons contribute to the actions of PYY3

36 in reducing food intake [86].
Amylin, released from pancreatic b cells, which also
release insulin, increases satiation via receptors expressed
in neurons of the area postrema [87]. These neurons project
to the NTS and PBN, nuclei forming part of the neural
circuit that mediates satiation. Whereas cholecystokinin
(CCK) reduces meal size, which is compensated by an
increase in meal frequency, chronic treatment of rodents
with amylin resulted in a reduction in meal size without
affecting meal frequency [87]. Pramlintide, a drug approved for the treatment of diabetics, is a human amylin
peptide derivative. A recent meta-analysis of pramlintide
treatment in diabetic and in obese subjects demonstrated
modest weight loss of 2.6 kg after treatment for at least 16
weeks [88].
Concluding remarks
Since the removal of drugs such as sibutramine and rimonabant from the market, the introduction of Qsymia and
lorcaserin brings a new perspective for the pharmacological treatment of obesity. These drugs pave the road for the
introduction of other anti-obesity drugs in the pipeline
such as Contrave and Empatic. Because animal models
have remarkably good predictive validity for the clinical
efficacy of anti-obesity drugs, more drug candidates are
likely to reach clinical testing in the near future. Many of
these novel drugs target multiple pathways involved in the
regulation of energy balance. This reflects the redundancy
in pathways involved in this important and fundamental
physiological process. In addition, there is large variability
in drug response, which may originate from individual
differences in the cause of obesity and the difficulty in
sustaining lifestyle changes. For the treatment of obesity, a
personalized medicine approach in which the right drug is
combined with personal lifestyle advice is expected to be
more successful than one treatment for all. Now that
multiple anti-obesity drugs are available, this has become
feasible.
Acknowledgments
I received grants from the European Union FP7 program (NeuroFast,
Full4Health, and I.Family) and from TI pharma and NeuroBasic. I thank
Drs J.M. Van Ree, L. van der Ploeg, and S.E. la Fleur for critical reading
of the manuscript before submission.

References
1 Ramirez-Zea, M. (2005) Validation of three predictive equations for
basal metabolic rate in adults. Public Health Nutr. 8, 12131228
2 Lenard, N.R. and Berthoud, H-R. (2008) Central and peripheral
regulation of food intake and physical activity: pathways and
genes. Obesity 16, S11S22
3 Williams, K.W. and Elmquist, J.K. (2012) From neuroanatomy to
behavior: central integration of peripheral signals regulating feeding
behavior. Nat. Neurosci. 15, 13501355
4 Valentino, M.A. et al. (2010) Central and peripheral molecular targets
for antiobesity pharmacotherapy. Clin. Pharmacol. Ther. 87, 652662
5 Derosa, G. and Maffioli, P. (2012) Anti-obesity drugs: a review about
their effects and their safety. Expert Opin. Drug Saf. 11, 459471
6 Dietrich, M.O. and Horvath, T.L. (2012) Limitations in anti-obesity
drug development: the critical role of hunger-promoting neurons. Nat.
Rev. Drug Discov. 11, 675691
7 Heal, D.J. et al. (2012) What is the prognosis for new centrally-acting
anti-obesity drugs? Neuropharmacology 63, 132146

Review
8 Witkamp, R.F. (2010) Current and future drug targets in weight
management. Pharm. Res. 28, 17921818
9 Aronne, L.J. and Thornton-Jones, Z.D. (2007) New targets for obesity
pharmacotherapy. Clin. Pharmacol. Ther. 81, 748752
10 Blundell, J.E. (1992) Serotonin and the biology of feeding. Am. J. Clin.
Nutr. 55, 155S159S
11 Halford, J.C.G. et al. (2011) Serotonergic anti-obesity agents: past
experience and future prospects. Drugs 71, 22472255
12 Sohn, J-W. et al. (2011) Serotonin 2C receptor activates a distinct
population of arcuate pro-opiomelanocortin neurons via TRPC
channels. Neuron 71, 488497
13 Lam, D.D. et al. (2007) Serotonin 5-HT2C Receptor agonist promotes
hypophagia via downstream activation of melanocortin 4 receptors.
Endocrinology 149, 13231328
14 Loos, R.J.F. et al. (2008) Common variants near MC4R are associated
with fat mass, weight and risk of obesity. Nat. Genet. 40, 768775
15 Yeo, G.S.H. and Heisler, L.K. (2012) Unraveling the brain regulation
of appetite: lessons from genetics. Nat. Neurosci. 15, 13431349
16 de Backer, M.W.A. et al. (2010) Melanocortin receptor-mediated
effects on obesity are distributed over specific hypothalamic
regions. Int. J. Obes. Relat. Metab. Disord. 35, 629641
17 Skibicka, K.P. and Grill, H.J. (2009) Hypothalamic and hindbrain
melanocortin receptors contribute to the feeding, thermogenic,
and cardiovascular action of melanocortins. Endocrinology 150,
53515361
18 Krishna, R. et al. (2009) Potent and selective agonism of the
melanocortin receptor 4 with MK-0493 does not induce weight loss
in obese human subjects: energy intake predicts lack of weight loss
efficacy. Clin. Pharmacol. Ther. 86, 659666
19 Greenfield, J.R. (2011) Melanocortin Signalling and the regulation of
blood pressure in human obesity. J. Neuroendocrinol. 23, 186193
20 Mashiko, S. et al. (2009) Synergistic interaction between neuropeptide
Y1 and Y5 receptor pathways in regulation of energy homeostasis.
Eur. J. Pharmacol. 615, 113117
21 Erondu, N. et al. (2006) Neuropeptide Y5 receptor antagonism does
not induce clinically meaningful weight loss in overweight and obese
adults. Cell Metab. 4, 275282
22 Atasoy, D. et al. (2012) Deconstruction of a neural circuit for hunger.
Nature 488, 172177
23 Wu, Q. et al. (2012) Deciphering a neuronal circuit that mediates
appetite. Nature 483, 594597
24 Yamamoto, T. (2006) Brain regions responsible for the expression of
conditioned taste aversion in rats. Chem. Senses 32, 105109
25 Wu, Q. et al. (2009) Loss of GABAergic signaling by AgRP neurons to
the parabrachial nucleus leads to starvation. Cell 137, 12251234
26 Marks, D.M. et al. (2008) Paroxetine: safety and tolerability issues.
Expert Opin. Drug Saf. 7, 783794
27 Elangbam, C.S. (2010) Drug-induced valvulopathy: an update.
Toxicol. Pathol. 38, 837848
28 ONeil, P.M. et al. (2009) Randomized placebo-controlled clinical trial
of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOMDM study. Obesity 20, 14261436
29 Wong, D. et al. (2012) The pharmaceutical market for obesity
therapies. Nat. Rev. Drug Discov. 11, 669670
30 Wellman, P.J. (2000) Norepinephrine and the control of food intake.
Nutrition 16, 837842
31 Valassi, E. et al. (2008) Neuroendocrine control of food intake. Nutr.
Metab. Cardiovasc. Dis. 18, 158168
32 Mansur, S.S. et al. (2011) a1 receptor antagonist in the median raphe
nucleus evoked hyperphagia in free-feeding rats. Appetite 57, 498503
33 Larsen, T.M. et al. (2002) Effect of a 28-d treatment with L-796568, a
novel b3-adrenergic receptor agonist, on energy expenditure and body
composition in obese men. Am. J. Clin. Nutr. 76, 780788
34 Arch, J.R.S. (2008) The discovery of drugs for obesity, the metabolic
effects of leptin and variable receptor pharmacology: perspectives
from b3-adrenoceptor agonists. Naunyn Schmiedebergs Arch.
Pharmacol. 378, 225240
35 Fruhbeck, G. et al. (2009) BAT: a new target for human obesity?
Trends Pharmacol. Sci. 30, 387396
36 Redman, L.M. et al. (2006) Lack of an effect of a novel 3-adrenoceptor
agonist, TAK-677, on energy metabolism in obese individuals: a
double-blind, placebo-controlled randomized study. J. Clin.
Endocrinol. Metab. 92, 527531

Trends in Neurosciences February 2013, Vol. 36, No. 2

37 Kang, J.G. et al. (2010) Randomized controlled trial to investigate the

effects of a newly developed formulation of phentermine diffusecontrolled release for obesity. Diabetes Obes. Metab. 12, 876882
38 Small, D.M. et al. (2003) Feeding-induced dopamine release in dorsal
striatum correlates with meal pleasantness ratings in healthy human
volunteers. Neuroimage 19, 17091715
39 Cooper, S.J. and Al-Naser, H.A. (2006) Dopaminergic control of food
choice: contrasting effects of SKF 38393 and quinpirole on highpalatability food preference in the rat. Neuropharmacology 50,
953963
40 Johnson, P.M. and Kenny, P.J. (2010) Dopamine D2 receptors in
addiction-like reward dysfunction and compulsive eating in obese
rats. Nat. Neurosci. 13, 635641
41 Wang, G-J. et al. (2001) Brain dopamine and obesity. Lancet 357,
354357
42 Palmiter, R.D. (2007) Is dopamine a physiologically relevant mediator
of feeding behavior? Trends Neurosci. 30, 375381
43 Tong, Y. and Pelletier, G. (1992) Role of dopamine in the regulation of
proopiomelanocortin (POMC) mRNA levels in the arcuate nucleus
and pituitary gland of the female rat as studied by in situ
hybridization. Brain Res. Mol. Brain Res. 15, 2732
44 Di Giovanni, G. et al. (1999) Selective blockade of serotonin-2C/2B
receptors enhances mesolimbic and mesostriatal dopaminergic
function: a combined in vivo electrophysiological and microdialysis
study. Neuroscience 91, 587597
45 ODell, L.E. (2004) Serotonin1B Receptors in the ventral tegmental
area modulate cocaine-induced increases in nucleus accumbens
dopamine levels. J. Pharmacol. Exp. Ther. 311, 711719
46 van der Hoek, G.A. and Cooper, S.J. (1994) The selective dopamine
uptake inhibitor GBR 12909: its effects on the microstructure of
feeding in rats. Pharmacol. Biochem. Behav. 48, 135140
47 Billes, S.K. and Cowley, M.A. (2006) Inhibition of dopamine and
norepinephrine reuptake produces additive effects on energy balance
in lean and obese mice. Neuropsychopharmacology 32, 822834
48 Billes, S.K. and Greenway, F.L. (2011) Combination therapy with
naltrexone and bupropion for obesity. Expert Opin. Pharmacother. 12,
18131826
49 Plodkowski, R.A. et al. (2009) Bupropion and naltrexone: a review of
their use individually and in combination for the treatment of obesity.
Expert Opin. Pharmacother. 10, 10691081
50 Astrup, A. et al. (2008) Effect of tesofensine on bodyweight loss, body
composition, and quality of life in obese patients: a randomised,
double-blind, placebo-controlled trial. Lancet 372, 19061913
51 Greenway, F.L. et al. (2009) Comparison of combined bupropion and
naltrexone therapy for obesity with monotherapy and placebo. J. Clin.
Endocrinol. Metab. 94, 48984906
52 Yeomans, M. and Gray, R. (2002) Opioid peptides and the control of
human ingestive behaviour. Neurosci. Biobehav. Rev. 26, 713728
53 Nogueiras, R. et al. (2012) The opioid system and food intake:
homeostatic and hedonic mechanisms. Obes. Facts 5, 196207
54 Greenway, F.L. et al. (2008) Rational design of a combination
medication for the treatment of obesity. Obesity 17, 3039
55 Will, M.J. et al. (2006) Pharmacological characterization of high-fat
feeding induced by opioid stimulation of the ventral striatum. Physiol.
Behav. 89, 226234
56 Sahr, A.E. et al. (2008) Activation of mesolimbic dopamine neurons
during novel and daily limited access to palatable food is blocked by
the opioid antagonist LY255582. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 295, R463R471
57 Clapham, J.C. (2012) Central control of thermogenesis.
Neuropharmacology 63, 111123
58 Gadde, K.M. et al. (2003) Zonisamide for weight loss in obese adults: a
randomized controlled trial. JAMA 289, 18201825
59 Gadde, K.M. et al. (2007) Combination therapy of zonisamide and
bupropion for weight reduction in obese women: a preliminary,
randomized, open-label study. J. Clin. Psychiatry 68, 12261229
60 Garvey, W.T. et al. (2012) Two-year sustained weight loss and
metabolic benefits with controlled-release phentermine/topiramate
in obese and overweight adults (SEQUEL): a randomized, placebocontrolled, phase 3 extension study. Am. J. Clin. Nutr. 95, 297308
61 Arima, H. and Oiso, Y. (2010) Positive effect of baclofen on body
weight reduction in obese subjects: a pilot study. Intern. Med. 49,
20432047
139

Review
62 Xu, Y. et al. (2012) Role of GABA release from leptin receptorexpressing neurons in body weight regulation. Endocrinology 153,
22232233
63 Vullo, D. et al. (2004) Carbonic anhydrase inhibitors. Inhibition of
mitochondrial isozyme V with aromatic and heterocyclic
sulfonamides. J. Med. Chem. 47, 12721279
64 Antel, J. and Hebebrand, J. (2011) Weight-reducing side effects of the
antiepileptic agents topiramate and zonisamide. Appetite Control 209,
433466
65 Kirkham, T.C. (2005) Endocannabinoids in the regulation of appetite
and body weight. Behav. Pharmacol. 16, 297313
66 Cota, D. et al. (2003) The endogenous cannabinoid system affects
energy balance via central orexigenic drive and peripheral
lipogenesis. J. Clin. Invest. 112, 423431
67 Di Marzo, V. et al. (2001) Leptin-regulated endocannabinoids are
involved in maintaining food intake. Nature 410, 822825
68 Hrabovszky, E. et al. (2012) Distribution of type 1 cannabinoid
receptor-expressing neurons in the septalhypothalamic region of
the mouse: colocalization with GABAergic and glutamatergic
markers. J. Comp. Neurol. 520, 10051020
69 Kunos, G. and Tam, J. (2011) The case for peripheral CB1 receptor
blockade in the treatment of visceral obesity and its cardiometabolic
complications. Br. J. Pharmacol. 163, 14231431
70 Jbilo, O. (2005) The CB1 receptor antagonist rimonabant reverses the
diet-induced obesity phenotype through the regulation of lipolysis and
energy balance. FASEB J. 11, 15671571
71 Christensen, R. et al. (2007) Efficacy and safety of the weight-loss drug
rimonabant: a meta-analysis of randomised trials. Lancet 370,
17061713
72 Tam, J. et al. (2012) Peripheral cannabinoid-1 receptor inverse
agonism reduces obesity by reversing leptin resistance. Cell Metab.
16, 167179
73 Meye, F.J. et al. (2012) Neutral antagonism at the cannabinoid 1
receptor: a safer treatment for obesity. Mol. Psychiatry http://
dx.doi.org/10.1038/mp.2012.145
74 Chronaiou, A. et al. (2012) Lower ghrelin levels and exaggerated
postprandial peptide-YY, glucagon-like peptide-1, and insulin
responses, after gastric fundus resection, in patients undergoing
Roux-en-Y gastric bypass: a randomized clinical trial. Obes. Surg.
22, 17611770
75 Cummings, D.E. (2004) Plasma ghrelin levels and hunger scores in
humans initiating meals voluntarily without time- and food-related
cues. Am. J. Physiol. Endocrinol. Metab. 287, E297E304
76 Cummings, D.E. et al. (2002) Plasma ghrelin levels after diet-induced
weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 16231630
77 Sumithran, P. et al. (2011) Long-term persistence of hormonal
adaptations to weight loss. N. Engl. J. Med. 365, 15971604
78 Delporte, C. (2012) Recent advances in potential clinical application of
ghrelin in obesity. J. Obes. 2012, 18
79 Yang, J. et al. (2008) Identification of the acyltransferase that
octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell
132, 387396
80 Taylor, M.S. et al. (2012) Ghrelin O-acyltransferase assays and
inhibition. Methods Enzymol. 514, 205228
81 Monami, M. et al. (2012) Effects of glucagon-like peptide-1 receptor
agonists on body weight: a meta-analysis. Exp. Diabetes Res. 2012,
18

140

Trends in Neurosciences February 2013, Vol. 36, No. 2

82 Astrup, A. et al. (2011) Safety, tolerability and sustained weight loss

over 2 years with the once-daily human GLP-1 analog, liraglutide. Int.
J. Obes. Relat. Metab. Disord. 36, 843854
83 De Silva, A. and Bloom, S.R. (2012) Gut hormones and appetite
control: a focus on PYY and GLP-1 as therapeutic targets in
obesity. Gut Liver 6, 10
84 Batterham, R.L. et al. (2002) Gut hormone PYY3-36 physiologically
inhibits food intake. Nature 418, 650654
85 Tschop, M. et al. (2004) Does gut hormone PYY336 decrease food
intake in rodents? Nature 430, 13
86 Acuna-Goycolea, C. (2005) Peptide YY336 inhibits both anorexigenic
proopiomelanocortin and orexigenic neuropeptide Y neurons:
implications for hypothalamic regulation of energy homeostasis. J.
Neurosci. 25, 1051010519
87 Lutz, T.A. (2012) Control of energy homeostasis by amylin. Cell. Mol.
Life Sci. 69, 19471965
88 Singh-Franco, D. et al. (2011) The effect of pramlintide acetate on
glycemic control and weight in patients with type 2 diabetes mellitus
and in obese patients without diabetes: a systematic review and metaanalysis. Diabetes Obes. Metab. 13, 169180
89 Rodgers, R.J. et al. (2012) Anti-obesity drugs: past, present and future.
Dis. Model Mech. 5, 621626
90 Li, Z. et al. (2005) Meta-analysis: pharmacologic treatment of obesity.
Ann. Intern. Med. 142, 532546
91 Weintraub, M. et al. (1992) Long-term weight control study. I (weeks 0
to 34). The enhancement of behavior modification, caloric restriction,
and exercise by fenfluramine plus phentermine versus placebo. Clin.
Pharmacol. Ther. 51, 586594
92 Connolly, H.M. et al. (1997) Valvular heart disease associated with
fenfluramine-phentermine. N. Engl. J. Med. 337, 581588
93 James, W.P.T. et al. (2000) Effect of sibutramine on weight
maintenance after weight loss: a randomised trial. Lancet 356,
21192125
94 Nelson, D.L. and Gehlert, D.R. (2006) Central nervous system
biogenic amine targets for control of appetite and energy
expenditure. Endocrine 29, 4960
95 Padwal, R.S. and Majumdar, S.R. (2007) Drug treatments for obesity:
orlistat, sibutramine, and rimonabant. Lancet 369, 7177
96 Kopelman, P. et al. (2009) Weight loss, HbA1c reduction, and
tolerability of cetilistat in a randomized, placebo-controlled phase 2
trial in obese diabetics: comparison with orlistat (Xenical). Obesity 18,
108115
97 Greenway, F.L. et al. (2010) Effect of naltrexone plus bupropion on
weight loss in overweight and obese adults (COR-I): a multicentre,
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
376, 595605
98 Levine, J.A. (2007) Nonexercise activity thermogenesis liberating
the life-force. J. Intern. Med. 262, 273287
99 Grill, H. (2002) The neuroanatomical axis for control of energy
balance. Front. Neuroendocrinol. 23, 240
100 Kelley, A.E. et al. (2005) A proposed hypothalamicthalamicstriatal
axis for the integration of energy balance, arousal, and food reward. J.
Comp. Neurol. 493, 7285
101 Hernandez, L. and Hoebel, B.G. (1989) Food intake and lateral
hypothalamic self-stimulation covary after medial hypothalamic
lesions or ventral midbrain 6-hydroxydopamine injections that
cause obesity. Behav. Neurosci. 103, 412422