The ups and downs of growth hormone secretagogue receptor signaling
María Paula Cornejo,Emilio Román Mustafá,Daniela Cassano,Jean-Louis Banères,Jesica Raingo,Mario Perello +5 more
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TLDR
The growth hormone secretagogue receptor (GHSR) has emerged as one of the most fascinating molecules from the perspective of neuroendocrine control as mentioned in this paper, and plays key roles regulating not only growth hormone secretion but also food intake, adiposity, body weight, glucose homeostasis and other complex functions.Abstract:
The growth hormone secretagogue receptor (GHSR) has emerged as one of the most fascinating molecules from the perspective of neuroendocrine control. GHSR is mainly expressed in the pituitary and the brain, and plays key roles regulating not only growth hormone secretion but also food intake, adiposity, body weight, glucose homeostasis and other complex functions. Quite atypically, GHSR signaling displays a basal constitutive activity that can be up- or downregulated by two digestive system-derived hormones: the octanoylated-peptide ghrelin and the liver-expressed antimicrobial peptide 2 (LEAP2), which was recently recognized as an endogenous GHSR ligand. The existence of two ligands with contrary actions indicates that GHSR activity can be tightly regulated and that the receptor displays the capability to integrate such opposing inputs in order to provide a balanced intracellular signal. This article provides a summary of the current understanding of the biology of ghrelin, LEAP2 and GHSR and discusses the reconceptualization of the cellular and physiological implications of the ligand-regulated GHSR signaling, based on the latest findings.read more
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Journal ArticleDOI
LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.
Kripa Shankar,Nathan P. Metzger,Omprakash Singh,Bharath K. Mani,Sherri Osborne-Lawrence,Salil Varshney,Deepali Gupta,Sean B. Ogden,Shota Takemi,Corine P. Richard,Karabi Nandy,Chen Liu,Jeffrey M. Zigman +12 more
TL;DR: The first known LEAP2-KO mouse line was generated in this paper, where the metabolic effects of genetic leaper-expressed antimicrobial peptide-2 (LEAP2) deletion were determined.
Journal ArticleDOI
LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men
Christoffer A. Hagemann,Malene Shin Jensen,Stephanie Holm,Lærke S. Gasbjerg,Sarah Byberg,Kirsa Skov-Jeppesen,Bolette Hartmann,Jens J. Holst,Flemming Dela,Tina Vilsbøll,Mikkel B. Christensen,Birgitte Holst,Filip K. Knop +12 more
TL;DR: The authors investigated the effects of exogenous LEAP2 on post-prandial glucose metabolism and ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men.
Journal ArticleDOI
Circulating ghrelin crosses the blood-cerebrospinal fluid barrier via growth hormone secretagogue receptor dependent and independent mechanisms.
Maia Uriarte,Pablo Nicolás de Francesco,Gimena Fernandez,Daniel Castrogiovanni,Micaela D'Arcangelo,Monica Imbernon,Sonia Cantel,Séverine Denoyelle,Jean-Alain Fehrentz,Jeppe Praetorius,Vincent Prevot,Mario Perello +11 more
TL;DR: In this paper, a variety of in vivo and in vitro studies were performed to test the hypothesis that the transport of ghrelin across the blood-CSF barrier occurs in a GHSR-dependent manner.
Journal ArticleDOI
LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling.
Emilio Román Mustafá,Santiago Cordisco Gonzalez,Marjorie Damian,Sonia Cantel,Séverine Denoyelle,Renaud Wagner,Helgi B. Schiöth,Helgi B. Schiöth,Jean-Alain Fehrentz,Jean-Louis Banères,Mario Perello,Jesica Raingo +11 more
TL;DR: In this article, the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on voltage-gated calcium channels type 2.2 (CaV2.2) was investigated.
Journal ArticleDOI
The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond
Mario Perello,María Paula Cornejo,Pablo Nicolás de Francesco,Gimena Fernandez,Laurent Gautron,Lesly S Valdivia +5 more
TL;DR: In this paper , the authors discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin, and conclude that studies using rats have provided the most congruent evidence indicating that the VN mediates some actions of Ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations.
References
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Journal ArticleDOI
Evidence Supporting a Role for the Blood-Cerebrospinal Fluid Barrier Transporting Circulating Ghrelin into the Brain.
Maia Uriarte,Pablo Nicolás de Francesco,Gimena Fernandez,Agustina Cabral,Daniel Castrogiovanni,Tyler Lalonde,Leonard G. Luyt,Sebastián A. Trejo,Mario Perello +8 more
TL;DR: Current evidence suggests that the blood-CSF barrier can transport circulating ghrelin into the brain, and that the access of ghrel in into the CSF is required for its full orexigenic effect.
Journal ArticleDOI
Structure and dynamics of G protein-coupled receptor-bound ghrelin reveal the critical role of the octanoyl chain.
Guillaume Ferré,Maxime Louet,Oliver Saurel,Bartholomé Delort,Georges Czaplicki,Céline M'Kadmi,Marjorie Damian,Pedro Renault,Sonia Cantel,Laurent Gavara,Pascal Demange,Jacky Marie,Jean-Alain Fehrentz,Nicolas Floquet,Alain Milon,Jean-Louis Banères +15 more
TL;DR: It is concluded that the ghrelin octanoyl chain is essential to form the hydrophobic core and promote access of gh Relin to the receptor ligand-binding pocket, involving the formation of a well-defined hydrophilic core.
Journal ArticleDOI
Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation.
AL Hopkins,Timothy A. S. Nelson,Irina A. Guschina,Lydia C. Parsons,Charlotte L. Lewis,Richard Charles Brown,Helen C. Christian,Jeffrey S. Davies,Timothy N. C. Wells +8 more
TL;DR: The adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R, which suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity.
Journal ArticleDOI
Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus.
TL;DR: The presence of GOAT and its ability to acylate non‐octanoylated ghrelin in the hippocampus will advance the understanding for the role of endogenous GOAT in the amygdala and facilitate the search for the source of ghrel in the brain that is intrinsic to the brain.
Journal ArticleDOI
Structural Model of Ghrelin Bound to its G Protein-Coupled Receptor.
Brian J. Bender,Gerrit Vortmeier,Stefan Ernicke,Mathias Bosse,Anette Kaiser,Sylvia Els-Heindl,Ulrike Krug,Annette G. Beck-Sickinger,Jens Meiler,Daniel Huster +9 more
TL;DR: The structural basis of ghrelin binding to GHSR was investigated using solid-state nuclear magnetic resonance spectroscopy, site-directed mutagenesis, and Rosetta modeling, and key residues in the peptide for receptor binding beyond the known motif were identified.
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