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Article ; Online: Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation.

Barrile, Franco / Cassano, Daniela / Fernandez, Gimena / De Francesco, Pablo N / Reynaldo, Mirta / Cantel, Sonia / Fehrentz, Jean-Alain / Donato, José / Schiöth, Helgi B / Zigman, Jeffrey M / Perello, Mario

Psychoneuroendocrinology

2023 Volume 156, Page(s) 106333

Abstract: Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin ... ...

Abstract	Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHA Methods: We investigated the distribution of LHA Conclusions: We provide a compelling neuroanatomical and functional characterization of LHA
MeSH term(s)	Mice ; Male ; Animals ; Hypothalamic Area, Lateral/metabolism ; Arcuate Nucleus of Hypothalamus/metabolism ; Ghrelin/pharmacology ; Ghrelin/metabolism ; Orexins ; Neurons/metabolism ; Receptors, Ghrelin/metabolism ; Eating
Chemical Substances	Ghrelin ; Orexins ; Receptors, Ghrelin
Language	English
Publishing date	2023-07-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	197636-9
ISSN	1873-3360 ; 0306-4530
ISSN (online)	1873-3360
ISSN	0306-4530
DOI	10.1016/j.psyneuen.2023.106333
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Article ; Online: The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond.

Perelló, Mario / Cornejo, María P / De Francesco, Pablo N / Fernandez, Gimena / Gautron, Laurent / Valdivia, Lesly S

IBRO neuroscience reports

2022 Volume 12, Page(s) 228–239

Abstract: Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are ... ...

Abstract	Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.
Language	English
Publishing date	2022-03-12
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	2667-2421
ISSN (online)	2667-2421
DOI	10.1016/j.ibneur.2022.03.003
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Article: Brain circuits mediating the orexigenic action of peripheral ghrelin: narrow gates for a vast kingdom.

Cabral, Agustina / De Francesco, Pablo N / Perello, Mario

Frontiers in endocrinology

2015 Volume 6, Page(s) 44

Language	English
Publishing date	2015
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2015.00044
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Article ; Online: Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner.

Andreoli, María F / Fittipaldi, Antonela S / Castrogiovanni, Daniel / De Francesco, Pablo N / Valdivia, Spring / Heredia, Florencia / Ribet-Travers, Carole / Mendez, Ignacio / Fasano, María V / Schioth, Helgi B / Doi, Suhail A / Habib, Abdella M / Perello, Mario

European journal of nutrition

2023 Volume 63, Issue 3, Page(s) 751–762

Abstract: ... in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).: Results ...

Abstract	Purpose: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations. Methods: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB). Results: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner. Conclusions: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans. Trial registration: The study was retrospectively registered in clinicaltrials.gov (April 2023). Clinicaltrials: gov Identifier: NCT05815641.
MeSH term(s)	Male ; Female ; Humans ; Hunger/physiology ; Ghrelin ; Hepcidins ; Appetite ; Obesity ; Sensation
Chemical Substances	Ghrelin ; Hepcidins
Language	English
Publishing date	2023-12-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1466536-0
ISSN	1436-6215 ; 1436-6207
ISSN (online)	1436-6215
ISSN	1436-6207
DOI	10.1007/s00394-023-03304-8
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Article ; Online: Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation.

Fernandez, Gimena / De Francesco, Pablo N / Cornejo, María P / Cabral, Agustina / Aguggia, Julieta P / Duque, Victor J / Sayar, Nilufer / Cantel, Sonia / Burgos, Juan I / Fehrentz, Jean-Alain / Rorato, Rodrigo / Atasoy, Deniz / Mecawi, André S / Perello, Mario

Endocrinology

2023 Volume 164, Issue 11

Abstract: The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a ... ...

Abstract	The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus-independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic-pituitary-adrenal neuroendocrine axis.
MeSH term(s)	Mice ; Male ; Animals ; Corticotropin-Releasing Hormone/metabolism ; Ghrelin/pharmacology ; Ghrelin/metabolism ; Paraventricular Hypothalamic Nucleus/metabolism ; Hypothalamo-Hypophyseal System/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Neurons/metabolism
Chemical Substances	Corticotropin-Releasing Hormone (9015-71-8) ; Ghrelin ; Proto-Oncogene Proteins c-fos
Language	English
Publishing date	2023-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqad154
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Article ; Online: GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner.

Fernandez, Gimena / Cabral, Agustina / De Francesco, Pablo N / Uriarte, Maia / Reynaldo, Mirta / Castrogiovanni, Daniel / Zubiría, Guillermina / Giovambattista, Andrés / Cantel, Sonia / Denoyelle, Severine / Fehrentz, Jean-Alain / Tolle, Virginie / Schiöth, Helgi B / Perello, Mario

Cellular and molecular life sciences : CMLS

2022 Volume 79, Issue 5, Page(s) 277

Abstract: Objective: Prolonged fasting is a major challenge for living organisms. An appropriate metabolic response to food deprivation requires the activation of the corticotropin-releasing factor-producing neurons of the hypothalamic paraventricular nucleus ( ... ...

Abstract	Objective: Prolonged fasting is a major challenge for living organisms. An appropriate metabolic response to food deprivation requires the activation of the corticotropin-releasing factor-producing neurons of the hypothalamic paraventricular nucleus (PVH Methods: We estimated the activation of the PVH Results: We found that food deprivation results in the activation of the PVH Conclusion: Food deprivation-induced activation of the PVH
MeSH term(s)	Animals ; Antimicrobial Cationic Peptides/metabolism ; Corticotropin-Releasing Hormone/metabolism ; Corticotropin-Releasing Hormone/pharmacology ; Eating ; Food Deprivation ; Ghrelin/metabolism ; Ghrelin/pharmacology ; Hypothalamo-Hypophyseal System/metabolism ; Male ; Mice ; Neurons/metabolism ; Paraventricular Hypothalamic Nucleus/cytology ; Paraventricular Hypothalamic Nucleus/metabolism ; Pituitary-Adrenal System/metabolism ; Receptors, Ghrelin/genetics ; Receptors, Ghrelin/metabolism
Chemical Substances	Antimicrobial Cationic Peptides ; Ghrelin ; Ghsr1a protein, mouse ; Leap2 protein, mouse ; Receptors, Ghrelin ; Corticotropin-Releasing Hormone (9015-71-8)
Language	English
Publishing date	2022-05-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04302-5
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Article ; Online: Ghrelin proteolysis increases in plasma of men, but not women, with obesity.

Fittipaldi, Antonela S / Castrogiovanni, Daniel / Lufrano, Daniela / Saenz, Camila / De Francesco, Pablo N / Lalonde, Tyler / Luyt, Leonard G / Cantel, Sonia / Fehrentz, Jean-Alain / Andreoli, María F / Perello, Mario

Life sciences

2022 Volume 313, Page(s) 121305

Abstract: ... ghrelin proteolysis were assessed in plasma before and after a test meal in 40 people (n = 21 males ... with normal weight (NW, n = 20) or overweight/obesity (OW/OB, n = 20).: Key findings: Preprandial ghrelin ...

Abstract	Aims: Since plasma ghrelin can undergo des-acylation and proteolysis, the aim of this study was to investigate the extent to which an enhancement of these reactions is associated to the decrease of ghrelin in plasma after food intake or in individuals with obesity. Main methods: we performed an intervention cross-sectional study, in which levels of ghrelin, desacyl-ghrelin (DAG), glucose, insulin, ghrelin des-acylation and ghrelin proteolysis were assessed in plasma before and after a test meal in 40 people (n = 21 males) with normal weight (NW, n = 20) or overweight/obesity (OW/OB, n = 20). Key findings: Preprandial ghrelin and DAG levels were lower, whereas preprandial ghrelin proteolysis was ∼4.6-fold higher in plasma of males with OW/OB. In males, ghrelin proteolysis positively correlated with glycemia. Ghrelin and DAG levels were also lower in females with OW/OB, but preprandial ghrelin proteolysis was not different between females with NW or OW/OB. Ghrelin and DAG levels decreased postprandially in males and females, independently of BMI, and ghrelin proteolysis increased postprandially ∼2 folds only in individuals with NW. Ghrelin des-acylation remained unaffected by BMI or feeding status in both sexes. Significance: Current study shows that ghrelin proteolysis increases in males with obesity as well as after meal in lean individuals. Therefore, ghrelin proteolysis may be an important checkpoint and, consequently, a putative pharmacological target to control circulating ghrelin levels in humans.
MeSH term(s)	Female ; Humans ; Male ; Cross-Sectional Studies ; Ghrelin/blood ; Ghrelin/metabolism ; Insulin ; Obesity/metabolism ; Overweight ; Sex Characteristics
Chemical Substances	Ghrelin ; Insulin
Language	English
Publishing date	2022-12-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2022.121305
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Article ; Online: Brain accessibility delineates the central effects of circulating ghrelin.

Perello, Mario / Cabral, Agustina / Cornejo, María P / De Francesco, Pablo N / Fernandez, Gimena / Uriarte, Maia

Journal of neuroendocrinology

2019 Volume 31, Issue 7, Page(s) e12677

Abstract: Ghrelin is a hormone produced in the gastrointestinal tract that acts via the growth hormone secretagogue receptor. In the central nervous system, ghrelin signalling is able to recruit different neuronal targets that regulate the behavioural, ... ...

Abstract	Ghrelin is a hormone produced in the gastrointestinal tract that acts via the growth hormone secretagogue receptor. In the central nervous system, ghrelin signalling is able to recruit different neuronal targets that regulate the behavioural, neuroendocrine, metabolic and autonomic effects of the hormone. Notably, several studies using radioactive or fluorescent variants of ghrelin have found that the accessibility of circulating ghrelin into the mouse brain is both strikingly low and restricted to some specific brain areas. A variety of studies addressing central effects of systemically injected ghrelin in mice have also provided indirect evidence that the accessibility of plasma ghrelin into the brain is limited. Here, we review these previous observations and discuss the putative pathways that would allow plasma ghrelin to gain access into the brain together with their physiological implications. Additionally, we discuss some potential features regarding the accessibility of plasma ghrelin into the human brain based on the observations reported by studies that investigate the consequences of ghrelin administration to humans.
MeSH term(s)	Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Brain/physiology ; Ghrelin/blood ; Ghrelin/physiology ; Humans ; Neurons/metabolism ; Neurons/physiology
Chemical Substances	Ghrelin
Language	English
Publishing date	2019-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1007517-3
ISSN	1365-2826 ; 0953-8194
ISSN (online)	1365-2826
ISSN	0953-8194
DOI	10.1111/jne.12677
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Article ; Online: Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice.

Aguggia, Julieta P / Cornejo, María P / Fernandez, Gimena / De Francesco, Pablo N / Mani, Bharath K / Cassano, Daniela / Cabral, Agustina / Valdivia, Spring / García Romero, Guadalupe / Reynaldo, Mirta / Fehrentz, Jean-Alain / Zigman, Jeffrey M / Perello, Mario

Psychoneuroendocrinology

2022 Volume 139, Page(s) 105716

Abstract: Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within ... ...

Abstract	Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.
MeSH term(s)	Animals ; Ghrelin/metabolism ; Hypothalamus, Posterior ; Mice ; Neurons/metabolism ; Nitric Oxide/metabolism ; Rats ; Receptors, Ghrelin/metabolism ; Signal Transduction
Chemical Substances	Ghrelin ; Ghsr1a protein, mouse ; Receptors, Ghrelin ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2022-03-09
Publishing country	England
Document type	Journal Article
ZDB-ID	197636-9
ISSN	1873-3360 ; 0306-4530
ISSN (online)	1873-3360
ISSN	0306-4530
DOI	10.1016/j.psyneuen.2022.105716
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Article ; Online: Rhinoxenus (Dactylogyridae) parasitizing piranhas (Serrasalmidae) at its southernmost limit of distribution (Paraná River, Argentina), with the description of two new species.

Rossin, María A / Francesco, Pablo N DE / Irigoitia, Manuel M / Scarabotti, Pablo A / Taglioretti, Verónica / Timi, Juan T

Anais da Academia Brasileira de Ciencias

2019 Volume 91, Issue 4, Page(s) e20190711

Abstract: ... provided. Rhinoxenus argentinensis n. sp. is characterized by having the male copulatory organ (MCO ... forming a triangular expansion. Rhinoxenus paranaensis n. sp. is characterized by having a MCO as a coiled ...

Abstract	Three piranha species, Serrasalmus maculatus, S. marginatus and Pygocentrus nattereri, living sympatrically in the lower Paraná River (Argentina) were examined searching for nasal monogeneans to know its diversity and distribution. Four species of monogeneans belonging to Rhinoxenus were found parasitizing the nasal cavities. Two new species are described, and new morphological data of 2 previously described species is provided. Rhinoxenus argentinensis n. sp. is characterized by having the male copulatory organ (MCO) as a coiled tube with a reel shaped-base; an elongated accessory piece articulated to base of MCO; a sinistral vagina with a sclerotized vestibule, and a sclerotized cap of the ventral anchor laterally modified forming a triangular expansion. Rhinoxenus paranaensis n. sp. is characterized by having a MCO as a coiled tube with a reel-shaped base; an accessory piece with an elongate proximal portion, a dilated distal portion with digitiform projections articulated to base of MCO; a sinistral vagina with 5-6 cuticular spine-shaped processes, and a sclerotized cap of the ventral anchor modified laterally forming a bilobate expansion. Additionally, multivariate discriminant analyses showed significant morphometric differences in the ventral anchors among Rhinoxenus species parasitizing 'piranhas '.
MeSH term(s)	Animal Distribution ; Animals ; Argentina ; Characiformes/parasitology ; Fish Diseases/parasitology ; Male ; Platyhelminths/anatomy & histology ; Platyhelminths/classification ; Platyhelminths/isolation & purification ; Rivers ; Trematode Infections/parasitology
Language	English
Publishing date	2019-12-02
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	2046885-4
ISSN	1678-2690 ; 0001-3765
ISSN (online)	1678-2690
ISSN	0001-3765
DOI	10.1590/0001-3765201920190711
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