Comment on:

Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? [Front Neurosci. 2015

Cassano, Tommaso

Gaetani, Silvana

Frontiers in Neuroscience

English

PubMed

Silvana Gaetani

Tommaso Cassano

Frontiers - Publisher Connector

FRONTIERS COMMENTARY
published: 09 August 2016
doi: 10.3389/fnins.2016.00369
Frontiers in Neuroscience | www.frontiersin.org 1 August 2016 | Volume 10 | Article 369
Edited by:
Gaurav Bedse,
Vanderbilt University, USA
Reviewed by:
Anna Maria Giudetti,
University of Salento, Italy
Abdul Basit,
Italian Institute of Technology, Italy
*Correspondence:
Tommaso Cassano
tommaso.cassano@unifg.it
Received: 09 June 2016
Accepted: 27 July 2016
Published: 09 August 2016
Citation:
Gaetani S and Cassano T (2016) From
Obesity Resistance to Obesity
Prediction and Prevention?
Front. Neurosci. 10:369.
doi: 10.3389/fnins.2016.00369
From Obesity Resistance to Obesity
Prediction and Prevention?
Silvana Gaetani 1 and Tommaso Cassano 2*
1Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, Rome, Italy, 2Department of
Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
Keywords: diet induced obesity, hypothalamus, neuropeptides, gene expression, DNA methylation, high fat diet
A commentary on
Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant
rats: possible targets for obesity prediction?
by Cifani, C., Micioni Di Bonaventura, M. V., Pucci, M., Giusepponi, M. E., Romano, A., Di
Francesco, A., et al. (2015). Front. Neurosci. 9:187. doi: 10.3389/fnins.2015.00187
Eating disorders and obesity are urgent public health problem with a high burden of diseases for
our societies. Core symptoms are unhealthy eating habits, with disturbances of eating behavior, and
inability to control body weight.
Food intake and energy balance are controlled as a complex, redundant, regulatory system
ensuring that the amount of ingested calories does not exceed what the body can safely handle and
that sufficient body fuel is stored as fat. The main brain regions integrating peripheral and central
signals of this system are the hypothalamus and the brainstem. Key hypothalamic neurons are those
co-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate eating,
and those expressing pro-opiomelanocortin (POMC) and cocain- and amphetamine-regulated
transcript (CART), which inhibit feeding (Barsh and Schwartz, 2002). These mechanisms have not
changed in the last 30 years (Richard, 2015), while dramatic changes occurred in the sensory side of
the control process. Increased palatability, variety, availability, and energy content of food created
an “obesogenic food environment” able to overwhelm the body regulatory system and cause an
“obesity epidemic” (Johnson and Wardle, 2014; Lipek et al., 2015).
Differences in the responsiveness to “external” food cues and “internal” homeostatic signals
might be at the crossroad between obesity resistance and obesity development, although the
mechanisms at the basis of these differences are not fully elucidated (Llewellyn and Wardle, 2015).
It is well-known that the regulation of chromatin structure can modulate the accessibility of
chromatin to transcription factors, thus regulating gene expression (Russo et al., 1996). This is
the core mechanism of the epigenetic control, through which environmental factors are able
to modulate the expression of the genotype into the phenotype influencing the progression of
different diseases, including eating disorders (Pucci et al., 2015 Addiction Biology). Silencing and
unsilencing of genes can occur via changes in DNA methylation, as well as through epigenetic
modifications at the level of the histones (Feng et al., 2007). Nutritional epigenomics have suggested
that in most cases the development of obesity and type2 diabetes might be attributed to stable
epigenetic alterations occurring in early nutrition, during gestation and lactation (Gallou-Kabani
and Junien, 2005). Whether similar mechanisms take place also in adulthood, following the
exposure to an “obesogenic” environment and whether they are involved in obesity development
remained less investigated.
This hypothesis was the aim of a recent study in an animal model of diet-induced-obesity
(DIO) by two Italian research teams, led by Carlo Cifani and Claudio D’Addario (Cifani
et al., 2015). The authors investigated the individual sensitivity to weight gain/resistance of
Gaetani and Cassano Obesity: From Resistance to Prevention?
adult male Sprague Dawley rats, exposed to a fat-enriched (45%)
hypercaloric (5.24 kcal/g) diet and evaluated the hypothalamic
gene expression and the epigenetic regulation of NPY, AgRP,
POMC, CART, and of two receptors, namely PPAR-γ and leptin
receptor (lepR). The authors focused on two different time-
points with respect to the exposure to a high-fat diet (HFD).
At the first one (5 weeks) two subsets of HFD-fed rats started
showing divergent body weight gains: One subset was slightly,
but significantly, heavier than control rats (receiving a standard
laboratory chow of 2.6 kcal/g), indicating the development of
the DIO phenotype, while the other subset maintained the same
body weight gain of control rats, showing an obesity-resistant
(DR) phenotype. At the second time point of 21 weeks these two
phenotypes were utmost evident, with DIO rats weighting 21%
more than DR rats. Orexygenic NPY and PPAR-γ genes resulted
to be up-regulated in DIO rats with respect to DR rats after 5
weeks of HFD exposure, but not at the latest time-point, and a
consistent increase in DNA methylation at specific sites of the
gene promoter was also observed for NPY. Conversely, POMC
expression was down-regulated in DIO rats when obesity was
present from several weeks and, also in this case, the authors
found a consistent change of DNA methylation at the gene
promoter for POMC. The interesting hypothetical interpretation
that the authors offer is that NPY and PPAR-γ might be
involved in the early events leading to the onset of the obese
phenotype, but not later, when obesity is established and likely
maintained by the reduction of POMC-derived signals, such, as,
for example melanocortins. In keeping with their hypothesis,
the epigenetic regulation of these gene expressions seems to be
transient and reversible. This finding is particularly new and open
novel perspectives in the attempt of dissecting the mechanisms
responsible for obesity development in modern societies.
Future studies should broaden these results, taking into
consideration also other possible targets in the hypothalamus,
as well as in other brain areas, and involved not only in the
homeostatic but also in the hedonic/emotional and psychiatric
aspects of eating. For example, a good set of candidate
genes might include oxytocin and oxytocin receptors, based
on the key role that the oxytocinergic system plays in the
metabolic/behavioral regulation of feeding and body weight as
well as in the social/emotional aspects that characterize obesity
and eating disorders (Romano et al., 2016). Another possible
target to be evaluated is the endocannabinoid/acylethanolamide
system for the accumulating evidence on its function in the
modulation of satiety, anxiety, mood tone and the possible
implication in “food addiction” (D’Addario et al., 2014; Romano
et al., 2014, 2015).
Our increasing understanding of the elegant interconnected
redundancy of the pathways governing energy homeostasis is
clearly pointing at the emerging need of influencing more
than one element of the system jointly to achieve effective
and safe weight reduction. The pharmacological manipulation
of epigenetic mechanisms might offer a unique opportunity to
target at once multiple marks, thus representing a promising
tool to achieve both obesity prevention and therapy. The idea
is basically that if it is possible to detect early changes in
the expression regulation of candidate genes via epigenetic
mechanisms, it would be possible to identify biomarkers and
to slow-down or even avoid the development of the disease by
contrasting such epigenetic modifications (Choi and Friso, 2010).
In the context of Cifani et al. paper, where it was observed an
increase in DNA methylation, it could be possible to suggest the
use of bioactive compounds able to inhibit DNA methylation,
such as genistein, found in many food products containing
soy, or other demethylating agents such as antisense DNA
methyltransferase (Choi and Friso, 2010).
Besides DNA methylation, other epigenetic alterations might
include histone acetylation, one of the most extensively studied
histone modifications controlled by the balance between locally
recruited complexes containing histone acetyl transferases
(HATs) and histone deacetylases (HDACs). Imbalance of the
HAT-HDAC equilibrium has been linked to a number of
diseases including cancer and obesity. The events causing the
HAT-HDAC imbalance are well-understood and have provided
a rationale for the development of HDAC inhibitors for
pharmacotherapies. Recent interest in HDAC inhibitors has
expanded into dietary compounds such as butyrate, a short-
chain fatty acid from fiber, diallyl disulfide, an organosulfur
compound from garlic, and sulforaphane, an isothiocyanate
found in cruciferous vegetables, exhibiting HDAC inhibitory
activity (Choi and Friso, 2010).
In summary, if obesity development is mostly linked to
wrong eating habits, oversize food portions and wrong dietary
choices, we should take the opportunity to dissect the molecular
mechanisms at the basis of obesity resistance in the same
“obesogenic environment” both to redirect eating habits toward
healthy and functional foods that can prevent obesity, both to
develop novel pharmacological tools able to correct the altered
mechanisms and combat obesity.
AUTHOR CONTRIBUTIONS
All authors listed, have made substantial, direct, and intellectual
contribution to the work, and approved it for publication.
REFERENCES
Barsh, G. S., and Schwartz, M. W. (2002). Genetic approaches to studying
energy balance: perception and integration. Nat. Rev. Genet. 3, 589–600. doi:
10.1038/nrg862
Choi, S. W., and Friso, S. (2010). Epigenetics: a new bridge between nutrition and
health. Adv. Nutr. 1, 8–16. doi: 10.3945/ an.110.1004
Cifani, C., Micioni Di Bonaventura, M. V., Pucci, M., Giusepponi, M. E., Romano,
A., Di Francesco, A., et al. (2015). Regulation of hypothalamic neuropeptides
gene expression in diet induced obesity resistant rats: possible targets for obesity
prediction? Front. Neurosci. 9:187. doi: 10.3389/fnins.2015.00187
D’Addario, C., Micioni Di Bonaventura, M. V., Pucci, M., Romano, A., Gaetani, S.,
Ciccocioppo, R., et al. (2014). Endocannabinoid signaling and food addiction.
Neurosci. Biobehav. Rev. 47, 203–224. doi: 10.1016/j.neubiorev.2014.0
8.008
Feng, J., Fouse, S., and Fan, G. (2007). Epigenetic regulation of neural
gene expression and neuronal function. Pediatr. Res. 61, 58R–63R. doi:
10.1203/pdr.0b013e3180457635
Frontiers in Neuroscience | www.frontiersin.org 2 August 2016 | Volume 10 | Article 369
Gaetani and Cassano Obesity: From Resistance to Prevention?
Gallou-Kabani, C., and Junien, C. (2005). Nutritional epigenomics of metabolic
syndrome: new perspective against the epidemic. Diabetes 54, 1899–1906. doi:
10.2337/diabetes.54.7.1899
Johnson, F., and Wardle, J. (2014). Variety, palatability, and obesity. Adv. Nutr. 5,
851–859. doi: 10.3945/an.114.007120
Lipek, T., Igel, U., Gausche, R., Kiess, W., and Grande, G. (2015). Obesogenic
environments: environmental approaches to obesity prevention. J. Pediatr.
Endocrinol. Metab. 28, 485–495. doi: 10.1515/jpem-2015-0127
Llewellyn, C., and Wardle, J. (2015). Behavioral susceptibility to obesity: gene-
environment interplay in the development of weight. Physiol. Behav. 152,
494–501. doi: 10.1016/j.physbeh.2015.07.006
Pucci, M., Micioni Di Bonaventura, M. V., Giusepponi, M. E., Romano,
A., Filaferro, M., MacCarrone, M., et al. (2015). Epigenetic regulation of
nociceptin/orphanin FQ and corticotropin-releasing factor system genes in
frustration stress-induced binge-like palatable food consumption. Addict Biol.
doi: 10.1111/adb.12303. [Epub ahead of print].
Richard, D. (2015). Cognitive and autonomic determinants of energy homeostasis
in obesity. Nat. Rev. Endocrinol. 11, 489–501. doi: 10.1038/nrendo.2015.103
Romano, A., Karimian Azari, E., Tempesta, B., Mansouri, A., Micioni Di
Bonaventura, M. V., Ramachandran, T. A., et al. (2014). High dietary fat
intake influences the activation of specific hindbrain and hypothalamic nuclei
by the satiety factor oleoylethanolamide. Physiol. Behav. 136, 55–62. doi:
10.1016/j.physbeh.2014.04.039
Romano, A., Tempesta, B., Micioni Di Bonaventura, M. V., and Gaetani,
S. (2016). From autism to eating disorders and more: the role of
oxytocin in neuropsychiatric disorders. Front. Neurosci. 9:497. doi:
10.3389/fnins.2015.00497
Romano, A., Tempesta, B., Provensi, G., Passani, M. B., and Gaetani, S. (2015).
Central mechanisms mediating the hypophagic effects of oleoylethanolamide
and N-acylphosphatidylethanolamines: different lipid signals? Front.
Pharmacol. 26:137. doi: 10.3389/fphar.2015.00137
Russo, V. E. A., Martienssen, R. A., and Riggs, A. D. (1996). Epigenetic
Mechanisms of Gene Regulation. Plainview, NY: Cold Spring Harbor Laboratory
Press.
Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2016 Gaetani and Cassano. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The
use, distribution or reproduction in other forums is permitted, provided the
original author(s) or licensor are credited and that the original publication in
this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Neuroscience | www.frontiersin.org 3 August 2016 | Volume 10 | Article 369


From Obesity Resistance to Obesity Prediction and Prevention?

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From obesity resistance to obesity prediction and prevention?

Comment on:
Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? [Front Neurosci. 2015

GAETANI, SILVANA

Archivio della ricerca- Università di Roma La Sapienza

FRONTIERS COMMENTARYpublished: 09 August 2016doi: 10.3389/fnins.2016.00369Frontiers in Neuroscience | www.frontiersin.org 1 August 2016 | Volume 10 | Article 369Edited by:Gaurav Bedse,Vanderbilt University, USAReviewed by:Anna Maria Giudetti,University of Salento, ItalyAbdul Basit,Italian Institute of Technology, Italy*Correspondence:Tommaso Cassanotommaso.cassano@unifg.itReceived: 09 June 2016Accepted: 27 July 2016Published: 09 August 2016Citation:Gaetani S and Cassano T (2016) FromObesity Resistance to ObesityPrediction and Prevention?Front. Neurosci. 10:369.doi: 10.3389/fnins.2016.00369From Obesity Resistance to ObesityPrediction and Prevention?Silvana Gaetani 1 and Tommaso Cassano 2*1Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, Rome, Italy, 2Department ofClinical and Experimental Medicine, University of Foggia, Foggia, ItalyKeywords: diet induced obesity, hypothalamus, neuropeptides, gene expression, DNA methylation, high fat dietA commentary onRegulation of hypothalamic neuropeptides gene expression in diet induced obesity resistantrats: possible targets for obesity prediction?by Cifani, C., Micioni Di Bonaventura, M. V., Pucci, M., Giusepponi, M. E., Romano, A., DiFrancesco, A., et al. (2015). Front. Neurosci. 9:187. doi: 10.3389/fnins.2015.00187Eating disorders and obesity are urgent public health problem with a high burden of diseases forour societies. Core symptoms are unhealthy eating habits, with disturbances of eating behavior, andinability to control body weight.Food intake and energy balance are controlled as a complex, redundant, regulatory systemensuring that the amount of ingested calories does not exceed what the body can safely handle andthat sufficient body fuel is stored as fat. The main brain regions integrating peripheral and centralsignals of this system are the hypothalamus and the brainstem. Key hypothalamic neurons are thoseco-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate eating,and those expressing pro-opiomelanocortin (POMC) and cocain- and amphetamine-regulatedtranscript (CART), which inhibit feeding (Barsh and Schwartz, 2002). These mechanisms have notchanged in the last 30 years (Richard, 2015), while dramatic changes occurred in the sensory side ofthe control process. Increased palatability, variety, availability, and energy content of food createdan “obesogenic food environment” able to overwhelm the body regulatory system and cause an“obesity epidemic” (Johnson and Wardle, 2014; Lipek et al., 2015).Differences in the responsiveness to “external” food cues and “internal” homeostatic signalsmight be at the crossroad between obesity resistance and obesity development, although themechanisms at the basis of these differences are not fully elucidated (Llewellyn and Wardle, 2015).It is well-known that the regulation of chromatin structure can modulate the accessibility ofchromatin to transcription factors, thus regulating gene expression (Russo et al., 1996). This isthe core mechanism of the epigenetic control, through which environmental factors are ableto modulate the expression of the genotype into the phenotype influencing the progression ofdifferent diseases, including eating disorders (Pucci et al., 2015 Addiction Biology). Silencing andunsilencing of genes can occur via changes in DNA methylation, as well as through epigeneticmodifications at the level of the histones (Feng et al., 2007). Nutritional epigenomics have suggestedthat in most cases the development of obesity and type2 diabetes might be attributed to stableepigenetic alterations occurring in early nutrition, during gestation and lactation (Gallou-Kabaniand Junien, 2005). Whether similar mechanisms take place also in adulthood, following theexposure to an “obesogenic” environment and whether they are involved in obesity developmentremained less investigated.This hypothesis was the aim of a recent study in an animal model of diet-induced-obesity(DIO) by two Italian research teams, led by Carlo Cifani and Claudio D’Addario (Cifaniet al., 2015). The authors investigated the individual sensitivity to weight gain/resistance ofGaetani and Cassano Obesity: From Resistance to Prevention?adult male Sprague Dawley rats, exposed to a fat-enriched (45%)hypercaloric (5.24 kcal/g) diet and evaluated the hypothalamicgene expression and the epigenetic regulation of NPY, AgRP,POMC, CART, and of two receptors, namely PPAR-γ and leptinreceptor (lepR). The authors focused on two different time-points with respect to the exposure to a high-fat diet (HFD).At the first one (5 weeks) two subsets of HFD-fed rats startedshowing divergent body weight gains: One subset was slightly,but significantly, heavier than control rats (receiving a standardlaboratory chow of 2.6 kcal/g), indicating the development ofthe DIO phenotype, while the other subset maintained the samebody weight gain of control rats, showing an obesity-resistant(DR) phenotype. At the second time point of 21 weeks these twophenotypes were utmost evident, with DIO rats weighting 21%more than DR rats. Orexygenic NPY and PPAR-γ genes resultedto be up-regulated in DIO rats with respect to DR rats after 5weeks of HFD exposure, but not at the latest time-point, and aconsistent increase in DNA methylation at specific sites of thegene promoter was also observed for NPY. Conversely, POMCexpression was down-regulated in DIO rats when obesity waspresent from several weeks and, also in this case, the authorsfound a consistent change of DNA methylation at the genepromoter for POMC. The interesting hypothetical interpretationthat the authors offer is that NPY and PPAR-γ might beinvolved in the early events leading to the onset of the obesephenotype, but not later, when obesity is established and likelymaintained by the reduction of POMC-derived signals, such, as,for example melanocortins. In keeping with their hypothesis,the epigenetic regulation of these gene expressions seems to betransient and reversible. This finding is particularly new and opennovel perspectives in the attempt of dissecting the mechanismsresponsible for obesity development in modern societies.Future studies should broaden these results, taking intoconsideration also other possible targets in the hypothalamus,as well as in other brain areas, and involved not only in thehomeostatic but also in the hedonic/emotional and psychiatricaspects of eating. For example, a good set of candidategenes might include oxytocin and oxytocin receptors, basedon the key role that the oxytocinergic system plays in themetabolic/behavioral regulation of feeding and body weight aswell as in the social/emotional aspects that characterize obesityand eating disorders (Romano et al., 2016). Another possibletarget to be evaluated is the endocannabinoid/acylethanolamidesystem for the accumulating evidence on its function in themodulation of satiety, anxiety, mood tone and the possibleimplication in “food addiction” (D’Addario et al., 2014; Romanoet al., 2014, 2015).Our increasing understanding of the elegant interconnectedredundancy of the pathways governing energy homeostasis isclearly pointing at the emerging need of influencing morethan one element of the system jointly to achieve effectiveand safe weight reduction. The pharmacological manipulationof epigenetic mechanisms might offer a unique opportunity totarget at once multiple marks, thus representing a promisingtool to achieve both obesity prevention and therapy. The ideais basically that if it is possible to detect early changes inthe expression regulation of candidate genes via epigeneticmechanisms, it would be possible to identify biomarkers andto slow-down or even avoid the development of the disease bycontrasting such epigenetic modifications (Choi and Friso, 2010).In the context of Cifani et al. paper, where it was observed anincrease in DNA methylation, it could be possible to suggest theuse of bioactive compounds able to inhibit DNA methylation,such as genistein, found in many food products containingsoy, or other demethylating agents such as antisense DNAmethyltransferase (Choi and Friso, 2010).Besides DNA methylation, other epigenetic alterations mightinclude histone acetylation, one of the most extensively studiedhistone modifications controlled by the balance between locallyrecruited complexes containing histone acetyl transferases(HATs) and histone deacetylases (HDACs). Imbalance of theHAT-HDAC equilibrium has been linked to a number ofdiseases including cancer and obesity. The events causing theHAT-HDAC imbalance are well-understood and have provideda rationale for the development of HDAC inhibitors forpharmacotherapies. Recent interest in HDAC inhibitors hasexpanded into dietary compounds such as butyrate, a short-chain fatty acid from fiber, diallyl disulfide, an organosulfurcompound from garlic, and sulforaphane, an isothiocyanatefound in cruciferous vegetables, exhibiting HDAC inhibitoryactivity (Choi and Friso, 2010).In summary, if obesity development is mostly linked towrong eating habits, oversize food portions and wrong dietarychoices, we should take the opportunity to dissect the molecularmechanisms at the basis of obesity resistance in the same“obesogenic environment” both to redirect eating habits towardhealthy and functional foods that can prevent obesity, both todevelop novel pharmacological tools able to correct the alteredmechanisms and combat obesity.AUTHOR CONTRIBUTIONSAll authors listed, have made substantial, direct, and intellectualcontribution to the work, and approved it for publication.REFERENCESBarsh, G. S., and Schwartz, M. W. (2002). Genetic approaches to studyingenergy balance: perception and integration. Nat. Rev. Genet. 3, 589–600. doi:10.1038/nrg862Choi, S. W., and Friso, S. (2010). Epigenetics: a new bridge between nutrition andhealth. Adv. Nutr. 1, 8–16. doi: 10.3945/ an.110.1004Cifani, C., Micioni Di Bonaventura, M. V., Pucci, M., Giusepponi, M. E., Romano,A., Di Francesco, A., et al. (2015). Regulation of hypothalamic neuropeptidesgene expression in diet induced obesity resistant rats: possible targets for obesityprediction? Front. Neurosci. 9:187. doi: 10.3389/fnins.2015.00187D’Addario, C., Micioni Di Bonaventura, M. V., Pucci, M., Romano, A., Gaetani, S.,Ciccocioppo, R., et al. (2014). Endocannabinoid signaling and food addiction.Neurosci. Biobehav. Rev. 47, 203–224. doi: 10.1016/j.neubiorev.2014.08.008Feng, J., Fouse, S., and Fan, G. (2007). Epigenetic regulation of neuralgene expression and neuronal function. Pediatr. Res. 61, 58R–63R. doi:10.1203/pdr.0b013e3180457635Frontiers in Neuroscience | www.frontiersin.org 2 August 2016 | Volume 10 | Article 369Gaetani and Cassano Obesity: From Resistance to Prevention?Gallou-Kabani, C., and Junien, C. (2005). Nutritional epigenomics of metabolicsyndrome: new perspective against the epidemic. Diabetes 54, 1899–1906. doi:10.2337/diabetes.54.7.1899Johnson, F., and Wardle, J. (2014). Variety, palatability, and obesity. Adv. Nutr. 5,851–859. doi: 10.3945/an.114.007120Lipek, T., Igel, U., Gausche, R., Kiess, W., and Grande, G. (2015). Obesogenicenvironments: environmental approaches to obesity prevention. J. Pediatr.Endocrinol. Metab. 28, 485–495. doi: 10.1515/jpem-2015-0127Llewellyn, C., and Wardle, J. (2015). Behavioral susceptibility to obesity: gene-environment interplay in the development of weight. Physiol. Behav. 152,494–501. doi: 10.1016/j.physbeh.2015.07.006Pucci, M., Micioni Di Bonaventura, M. V., Giusepponi, M. E., Romano,A., Filaferro, M., MacCarrone, M., et al. (2015). Epigenetic regulation ofnociceptin/orphanin FQ and corticotropin-releasing factor system genes infrustration stress-induced binge-like palatable food consumption. Addict Biol.doi: 10.1111/adb.12303. [Epub ahead of print].Richard, D. (2015). Cognitive and autonomic determinants of energy homeostasisin obesity. Nat. Rev. Endocrinol. 11, 489–501. doi: 10.1038/nrendo.2015.103Romano, A., Karimian Azari, E., Tempesta, B., Mansouri, A., Micioni DiBonaventura, M. V., Ramachandran, T. A., et al. (2014). High dietary fatintake influences the activation of specific hindbrain and hypothalamic nucleiby the satiety factor oleoylethanolamide. Physiol. Behav. 136, 55–62. doi:10.1016/j.physbeh.2014.04.039Romano, A., Tempesta, B., Micioni Di Bonaventura, M. V., and Gaetani,S. (2016). From autism to eating disorders and more: the role ofoxytocin in neuropsychiatric disorders. Front. Neurosci. 9:497. doi:10.3389/fnins.2015.00497Romano, A., Tempesta, B., Provensi, G., Passani, M. B., and Gaetani, S. (2015).Central mechanisms mediating the hypophagic effects of oleoylethanolamideand N-acylphosphatidylethanolamines: different lipid signals? Front.Pharmacol. 26:137. doi: 10.3389/fphar.2015.00137Russo, V. E. A., Martienssen, R. A., and Riggs, A. D. (1996). EpigeneticMechanisms of Gene Regulation. Plainview, NY: Cold Spring Harbor LaboratoryPress.Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2016 Gaetani and Cassano. This is an open-access article distributedunder the terms of the Creative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is permitted, provided theoriginal author(s) or licensor are credited and that the original publication inthis journal is cited, in accordance with accepted academic practice. No use,distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Neuroscience | www.frontiersin.org 3 August 2016 | Volume 10 | Article 369

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