Role of Orexin System in Obesity

Abstract

Obesity is a public health disease and its incidence is steadily increasing both in adults and in children especially in the Western World. It is important to understand the underlying mechanisms of obesity and possible treatments as the orexin system with its receptors, which are involved in different physiological processes. In fact, the aim of this mini-review is to consider the importance of the orexin system and the role that orexin plays in the regulation of obesity and physical activity. Furthermore to demonstrate how the orexin and its receptors fit within a network distributed in multiple brain areas, each with specific actions, whose activation and interconnection has been seen to lead to a lower propensity for increase of fat mass, it could thus constitute an important future target for prevention and treatment of obesity.

Full text

Mini Review Open Access
Biology and Medicine
Messina et al., Biol Med (Aligarh) 2015, 7:4
http://dx.doi.org/10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Keywords: Orexin; Obesity; Energy expenditure
Introduction
e orexin (hypocretin) is an important neurotransmitter in the
regulation of sleep-wakefulness and appetite. ere are two types of
orexin peptides: the orexin-A (OXA or hypocretin 1) and orexin-B
(OXB or hypocretin 2). e majority of the orexin peptides are
synthesized in neurons located in the lateral and back hypothalamus
and they send projections throughout the brain regions [1,2]. ese
peptides derive from the prepro-orexin (prepro hypocretin) gene,
which encodes a precursor (130 amino acids in
rodents, 131 residues in
humans) that is cleaved into orexin-A (synonymous with hypocretin-1;
33 amino acids) and
orexin-B (hypocretin-2; 28 residues (Figure 1).
e orexin binds to two types of receptors, belonging to the class of
G protein-coupled receptors: orexin receptor type-1 (OX1R or hypo-
cretin receptor 1) and orexin receptor type-2 (OX2R or hypocretin
receptor 2) Both orexin receptors subtypes can bind to OXA and OXB,
but with dierential anity; in particular orexin receptor type-1 has a
higher anity for OXA, while orexin receptor type- 2 has equal anity
for either orexin peptide [3,4] (Figure 1).
Orexin neurons have a lot of projections related to many and dier-
ent brain regions, as well as for the orexin receptors that are expressed
in several areas of the brain [1,2]. A similar distribution of orexin neu-
rons and their receptors explains how these neurotransmitters are
involved in numerous physiological processes, including the modula-
tion of the sleep, the arousal and of the energy expenditure, suggesting
an important role in development of obesity [5–8] (Figure
2). In this review we want to highlight that the orexin system can lead
to an increase in energy expenditure and so give a contribute to the
obesity resistance. We want to provide a synthesis of the current state of
knowledge in the regulation of hypothalamic orexin during obesity and
provide a platform on which to develop an improved clinical outcomes
during obesity in relation to the autonomic nervous system, brown adi-
pose tissue, sleep-wake rhythm, expenditure energy.
e way of the action of the orexin system depends on a series of
signals to multiple brain regions, and it is extremely important to un-
derstand the anatomy and function of the neuronal network of orexin
system. e proof of the fact the orexins peptides are involved into
energy metabolism is exemplied in a mouse model that exhibits post-
natal loss of orexin neurons [5]. In these mice, the orexin pro-
moter drives expression of the neurodegenerative gene ataxin-3 and
leading to progressive loss of the orexin neurons during development.
ese mice show hypophagia, lower levels of spontaneous physical
activity (SPA) and express the appearance of a obesity state when
fed a regular diet [5,8,9]. is indicates that an important function
of the orexins peptides is to rule energy expenditure and so modulate
food intake. A further support for this idea comes from other mouse
models in which the results prove that these mice show resistance to
high-fat diet–induced obesity, corroborating with the role of orexin
in promoting energy expenditure [10,11].
Orexin System and Neural Network
*Corresponding author: Prof. Marcellino Monda, MD, Department of Experimental
Medicine, Section of Human Physiology, and Clinical Dietetic Service, Second
University of Naples, Via Costantinopoli 16, 80138 Naples, Italy, Tel: +39 +81 566
5804; Fax +39 +81 5665841; E-mail: marcellino.monda@unina2.it
Received July 21, 2015; Accepted August 31, 2015; Published September 07, 2015
Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015)
Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi: 10.4172/0974-
8369.1000248
Copyright: © 2015 Messina G, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Role of Orexin System in Obesity
Giovanni Messina1, Vincenzo Monda1, Fiorenzo Moscatelli2,3, Anna A. Valenzano2, Giuseppe Monda1, Teresa Esposito1, Saverio De Blasio1,
Antonietta Messina1, Domenico Tafuri4, Maria Rosaria Barillari5, Giuseppe Cibelli2, Sergio Chief1, Bruno Varriale1 and Marcellino Monda1*
1Department of Experimental Medicine, Section of Human Physiology and Clinical Dietetic Service, Second University of Naples, 16 Costantinopoli Str., 80100 Naples, Italy
2Department of Clinical and Experimental Medicine, University of Foggia, 1 L. Pinto Avenue, 71122 Foggia, Italy
3Department of Human Movement and Sport Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
4Department of Motor Sciences and Wellness, University of Naples "Parthenope", 40 Medina Str., 80100 Naples, Italy
5Division of Audiology and Phoniatrics, Second University of Naples (SUN) via L. De Crecchio,3,80138, Naples, Italy
Abstract
Obesity is a public health disease and its incidence is steadily increasing both in adults and in children especially
in the Western World. It is important to understand the underlying mechanisms of obesity and possible treatments as
the orexin system with its receptors, which are involved in different physiological processes. In fact, the aim of this
mini-review is to consider the importance of the orexin system and the role that orexin plays in the regulation of obesity
and physical activity. Furthermore to demonstrate how the orexin and its receptors t within a network distributed
in multiple brain areas, each with specic actions, whose activation and interconnection has been seen to lead
to a lower propensity for increase of fat mass, it could thus constitute an important future target for prevention and
treatment of obesity.
Figure 1: Composition of Orexin-A and Orexin-B. OX1R: orexin receptor type-
1. OX2R: orexin receptor type-2.

Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015) Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi:
10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Page 2 of 6
Over the location in the lateral hypothalamus, which were initial-
ly described, the orexin and its receptors have been highlighted in
neuronal bodies and positive bers present in dierent regions of
the central nervous system (CNS) and their position is in connection
with the functions performed. erefore a lot of brain sites join in this
regulatory network through a signicant number of neurotransmitters
(Figure 3). e functions of the orexin system are expressed in dier-
ent brain regions, they control the same behaviors; in fact many of
the brain sites that participate in the SPA network also participate
in regulatory networks for food intake and other aspects of energy
balance. Several brain regions receive orexinergic input and express the
OXR and this instance suggests that the behavioral outcomes of the
orexin system are due to simultaneous activation of the OXR in dif-
ferent brain regions connected through projections.
Orexins are produced in a particular area of the hypothalamus,
including the caudal lateral hypothalamus and adjacent perifornical
area [12] and, from these sites, orexin projects throughout the other
areas of the brain. On the basis of anatomical predisposition appears
to be valid the hypothesis that the eects of the action of the orexin
system derive from a series of parallel signals that come from dierent
brain regions [13]. It is important to know that orexin neurons are in a
baseline intrinsic state of depolarized activity [14] and are highly inu-
enced by local conditions in an intralateral hypothalamic local network
[15]. e Activation of the OXR causes depolarization and active
neuronal ring by four possible mechanisms:
• activation of non-specic cationic currents
• activation of the Na+/Ca2+ exchanger
• phosphorylation-dependent inhibition of inwardly rectifying
K+ channels
• increase in Ca2+ through activation of L- and N-type Ca2+channels
[16–20].
e type of mechanism appears to be cell-dependent and both
orexin subtypes can couple to many G- proteins that cause neuronal
depolarization through many mechanisms cell-specic (Figure 4).
e Role Of Orexin In Brown Adipose Tissue
ermogenesis And Activation Of Sympathetic Nervous
System
Orexin system also inuences body temperature. In fact, an
Intracerebroventricular (icv) administration of orexin system induces
an increase in the ring rate of the sympathetic nerves to interscapular
brown adipose tissue (IBAT), accompanied with a rise in IBAT and
colonic temperatures [21]. In addition, the presence of orexin receptors
in many cerebral areas suggests that additional functions are played
by orexin system [22]. In general, those experiments demonstrate that
an icv injection of orexin system increases the temperature of IBAT,
which is the most important eect or of non shivering thermogenesis
in the rat [23], illustrating that the rise in heat production is also
due to the activation of thermogenesis unrelated to muscle activity.
IBAT activity is controlled by the sympathetic nervous system, and
factors, which inuence thermogenesis, appear to act centrally to
modify the sympathetic outow to IBAT [24]. e increase in colonic
temperature emphasizes the eect of orexin system on the “core”
temperature conrming the inclusion of orexin system among the
peptides controlling body temperature. e rise of the sympathetic
discharge induced by orexin system is corroborated by the increase in
heart rate, although a possible reduction on the vagal tone cannot be
excluded. Since Van Den Pol [25] demonstrated a direct innervation
of the intermedio lateral column of spinal cord by orexin-bers, there
might be another direct pathway of the orexin induced activation of the
sympathetic nervous system.
Materials and Methods
Animals
Most of the animal studies were conducted on Sprague-Dawley rats,
3 months old and weighing 250–300 g were used in the experiments.
e rats were housed in pairs at controlled temperature (22 ± 1°C) and
humidity (70%) with a 12:12 h light–dark cycle with light from 07:00
to 19:00 h. e experiments were in accordance with the European
Communities Council Directive of 24 November 1986 (86/609/EEC).
Figure 2: Effects of orexins in peripheral tissue and central nervous system.
and development of obesity. Adapted from Messina
et al., [8].
Figure 3: Brain neurotransmitters. OX1R: orexin receptor type-1. OX2R: orexin
receptor type-2.
Figure 4: Neuronal depolarization. OX1R: orexin receptor type-1. OX2R:
orexin receptor type-2.

Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015) Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi:
10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Page 3 of 6
tor in determining this variability is physical activity, and specically a
component of total energy expenditure known as nonexercise induced
thermogenesis (NEAT) (Figure 4) [31–33]. NEAT includes all forms
of energy expenditure not associated with formal exercise and it is
related with the concept of spontaneous physical activity (SPA) that
is utilized to describe “any type of physical activity that does not qualify
as voluntary exercise” [34–42].
Orexin role in sleep regulation and obesity
Many animal studies also support the idea that disordered sleep
may contribute to obesity. For example, following weight gain on a
high fat diet, obese mice showed increased time spent in slow wave
sleep (SWS) [43], while time spent in wakefulness was decreased and
the time spent in SWS was increased especially in the dark (active)
period. In this model, greater body weight was positively correlated
with more time spent in SWS, and negatively correlated with time spent
in wakefulness in the dark period. Obesity is associated with decreased
levels of orexin [44]. Orexin system regulates and consolidates sleep/
wake patterns. Narcoleptic patients, who lack orexin, have altered
sleep patterns, highly fragmented sleep and elevated body mass index
[45], which highlights the importance of orexin in maintaining normal
sleep/wake patterns and energy homeostasis. us alterations in orexin
levels might be related to disordered sleep regulation observed in obese
humans and animal models.
A decade ago Levin and colleagues showed that, when exposed
to high fat diet, more than half of out-bred Sprague-Dawley (SD)
rats developed diet-induced obesity, while the rest of the rats showed
resistance to diet-induced obesity [46]. Previously we showed greater
spontaneous physical activity (SPA), orexin sensitivity and orexin
receptor mRNA in the lateral hypothalamus of these obesity resistant
(OR) rats [47]. Relative to OR rats, SD rats had reduced orexin levels,
sleep fragmentation, decreased physical activity and became obese with
age [48].
Since obesity has been associated with poor sleep quality, obesity
resistance might be associated with better sleep quality, characterized
by consolidated sleep/wake states.
Sleep/wake patterns in ORR rats have been associated with elevated
orexin receptor proles in brain regions involved the regulation of
vigilance states. In some studies have been measured 24h sleep/wake
patterns and orexin receptor mRNA proles in brain sites involved in
sleep regulation, in OR and normally obesity susceptible SD rats at three
months of age, an age when their weight gain proles were signicantly
dierent. Obesity resistant rats spend greater time awake primarily
during the dark phase, have fewer number of and greater duration of
sleep/wake episodes, less frequent transitions between dierent sleep/
wake states, and a lower sleep drive.
ese results indicate that during the normal active period, OR
rats spent more time awake and had better sleep quality than obesity
susceptible SD rats. is study lends additional support to our
hypothesis that increased orexin signaling in sleep/wake regulatory
sites enhances sleep quality and positively inuences obesity resistance.
Orexin role in obesity and resting energy expenditure
Orexin system has a primary role in relation to obesity; in fact some
pharmacological studies have demonstrated that icv injections of both
orexin types have increased food intake and locomotor activity [49–
53]. A polygenic obesity model of rats, the obesity-prone (OP) and
obesity-resistant (OR) rats, derived by inbreeding from Sprague Daw-
Apparatus
A pair of silver wire electrodes recorded the ring rate of nerves
to IBAT. e electrical pulses were amplied by a condenser-coupled
amplier and were ltered by band-pass lters (NeuroLog System,
Digitimer). e raw pulses were displayed on an oscilloscope
(Tektronix) and sent to a window discriminator. Square waves from
the discriminator were sent to an analog-digital converter (DAS
system, Keithley) and stored on a computer (Personal Computer AT,
IBM) every 5 s. A rate meter with a reset time of 5 s was also used to
observe the time course of the nerve activity recorded by pen recorder
(Dynograph, Beckman). Because signal-to-noise ratio depended on the
number of nerve laments and the condition of contact between nerve
and electrodes, the basal burst rates were dierent for each rat. e
threshold level of the event detector was xed during the experiment
at 50% of the peaks of the largest pulses and above background noise.
ermocouples (Ellab) were used to monitor colonic and IBAT
temperatures (Tc and TIBAT) and the values were stored on a chart
recorder.
Two electrodes applied to the forelegs monitored the heart
rate (beats/min). Electrical signals were addressed to a poly- graph
(Dynograph, Beckman) to record the electrocardiograph- ic activity on
the card and on a computer disk.
Procedure
Usually the animals were anesthetized with ip pentobarbital (50
mg/kg bw) and a 20-gauge stainless guide cannula was positioned
stereotaxically above a lateral cerebral ventricle at the following
coordinates: 1.7 mm lateral to the midline, 0.4 mm posterior to the
bregma, 3.0 mm from the cranial theca. Nerve activity was recorded by
small nerve bundles dissected from the intercostal nerves supplying the
right side of IBAT. Nerve laments were isolated from the central cut
end of these nerve bundles under a dissecting microscope; the eerent
activity was recorded with a pair of silver wire electrodes. e nerve
laments were covered with a mixture of vaseline and liquid petroleum
at 37°C to avoid dehydration. At the same time as the nerve activity
was recorded the heart rate, Tc and TIBAT were monitored. Tc was
measured by inserting the thermocouple into the colon 4 cm from the
anus, while TIBAT was monitored by inserting the thermocouple in the
le side of IBAT. Orexin was icv injected into the cerebral ventricle in
rats which had received a drug or saline alone. e drugs were delivered
into the cerebral ventricle by gravity ow over a 2 min interval. e
cannula was 0.4 mm longer than the guide cannula.
Concept of obesity and its interindividual variability
Obesity (body mass index ≥ 30 kg of body weight/m2 of height) is
a medical condition characterized by the accumulation of excess free
fat [13] that can lead negative eects on health, resulting in a reduced
life expectancy and increased health problems. Obesity incidence in
adults and children has increased in the last twenty years, especially
in developed societies [26,27]. It is related to other diseases, including
cardiovascular dysfunction, diabetes mellitus type 2, disorders of the
osteo-articular system, stroke, metabolic syndrome and certain types
of cancer [28]. Obesity is most commonly caused by a combination of
excessive food intake, deciency of physical activity and genetic suscep-
tibility, enough to be considered a multifactorial disease.
e genetic component in the etiopathogenesis of obesity has as-
sumed in last years an important role by identifying an increasing
number of genes involved in the disease. e obesity in the humans
can depend by dierent genetic factors [29,30], but the major fac-

Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015) Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi:
10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Page 4 of 6
utes to their obesity resistant phenotype. Indeed, it was seen that
injections of orexin A in multiple brain sites increase levels of SPA
with a consequent increase of the food intake, which should lead
to a condition of obesity. Instead, the activation of the orexin system
increases energy expenditure and has a protective eect against obesity.
To demonstrate this, has been performed studies on rats through the
implantation of cannulae into RLH were given graded dose of OXA.
Aer postinjection were measured SPA and food intake and, as
expected, the result was that both components increased. At this
point OR rats maintained a lean phenotype, suggesting that the
negative caloric benet of OXA-induced SPA appears to outweigh the
positive calories due to OXA-induced hyperphagia. Furthermore, other
studies have shown that OR rats have higher endogenous SPA and are
more sensitive to other SPA-promoting stimuli and appear to be intrin-
sically protected from treatments that lower SPA, such as high-fat diet
feeding. en, while OP rats manifest lower SPA levels aer high-fat
diet consumption, OR rats maintain high basal SPA levels and have
greater OXA-induced SPA aer high fat diet feeding [65]. Finally, it is
worth remembering that over the orexin, other neurotransmitters are
able to inuence SPA levels, such as cholecystokinin, corticotrophin
releasing hormone and leptin, but orexin is the most consistent across
all brain sites and types of stimulation.
Conclusion
Orexin system leads to an increase of energy expenditure and SPA
levels. A fundamental point of this review is the evidence that higher
orexin signaling provides resistance to the development of obesity
and this is possible through dierent mechanisms like an increase in
synthesis or release of orexin peptides or changes in expression of the
orexin receptor. It is important to understand the concept of orexin
and its role in obesity resistance to nd new therapeutic and preventive
solutions against the excess body weight, in fact the stimulation of
orexin receptors may be a valid therapeutic approach together with ap-
propriate low-calorie diet, frequent physical exercise and psychological
proposal in order to build the foundation for preventive and curative
therapy against obesity.
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thermogenesis; TEF = thermic
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et al. [63].

Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015) Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi:
10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Page 5 of 6
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Citation: Messina G, Monda V, Moscatelli F, Valenzano AA, Monda G, et al. (2015) Role of Orexin system in obesity. Biol Med (Aligarh) 7: 248. doi:
10.4172/0974-8369.1000248
Volume 7 • Issue 4 • 1000248
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Page 6 of 6
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Citation: Andocs G, Rehman MU, Zhao QL, Papp E, Kondo T, et al. (2015)
Nanoheating without Articial Nanoparticles Part II. Experimental Support of the
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