The ups and downs of growth hormone secretagogue receptor signaling

Cornejo, María Paula; Mustafá, Emilio Román; Cassano, Daniela; Banères, Jean-Louis; Raingo, Jesica; Perelló, Mario

doi:10.1111/febs.15718

Cited by 25 publications

(31 citation statements)

References 153 publications

(293 reference statements)

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“…Interestingly, LEAP2 and ghrelin display similar binding affinities for GHSR ( Ge et al, 2018 ; M'Kadmi et al, 2019 ; Wang et al, 2019 ), but plasma LEAP2 levels are ∼10-fold higher than plasma ghrelin levels in satiated rodents and humans ( Mani et al, 2019 ; Fittipaldi et al, 2020 ). Thus, modulatory actions of LEAP2 on GHSR, such as those revealed here, may play a more dramatic role than ghrelin itself in some physiological GHSR functions ( Cornejo et al, 2021 ). On the other hand, plasma ghrelin mainly acts on brain targets near the fenestrated capillaries, such the hypothalamic arcuate nucleus or the area postrema ( Schaeffer et al, 2013 ; Cabral et al, 2014 ; Cabral et al, 2017 ).…”

Section: Discussionmentioning

confidence: 84%

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LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

et al. 2021

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The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.

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Section: Discussionmentioning

confidence: 84%

“…The bioactive portion of LEAP2 resides at the N-terminal region of the peptide, which binds to GHSR and impairs both ghrelin-evoked and constitutive signaling pathways ( M'Kadmi et al, 2019 ). Thus, GHSR activity is regulated by at least two endogenous ligands, ghrelin and LEAP2, that display opposite actions ( Cornejo et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

et al. 2021

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“…Setting aside the findings in the latter four studies, the aforementioned data led to the hypothesis that LEAP2 might offset the actions of acyl-ghrelin and contribute to the state of ghrelin resistance associated with obesity [ [20] , [21] , [22] , [23] ]. For example, acyl-ghrelin fails to acutely induce food intake in diet-induced obese mice and in obese Agouti mice whether acutely or chronically administered [ [24] , [25] , [26] ].…”

Section: Introductionmentioning

confidence: 99%

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

Shankar

Metzger

Singh

et al. 2021

Molecular Metabolism

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Objective The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. Methods We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. Results LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2–119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O 2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. Conclusions LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion...

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“…Ghrelin is a peptide hormone that operates through the binding and activation of the G protein-coupled receptor (GPCR) named growth hormone secretagogue receptor (GHSR). GHSR regulates various key physiological processes in particular the ones related to energy homeostasis including glucose metabolism [1,2]. Indeed, ghrelin administration induces blood glucose elevation and reduction in circulating insulin in humans and rodents [3].…”

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confidence: 99%

“…We previously reported that LEAP2 displays Ki value within the nanomolar range (1.26 AE 0.05 nM) and a pA 2 value of 7.99 AE 0.15 with respect to Gq-induced intracellular calcium mobilization [6]. Since then, a great deal of studies devoted to delineating LEAP2 function indicated that this peptide counteracts ghrelin-mediated actions including food intake and growth hormone secretion in rodent models [2,5,6,8]. Despite this rapid progress in characterizing LEAP2 activity, the effect of this peptide on glucose-stimulated insulin secretion is unknown.…”

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confidence: 99%

Liver‐Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets

Bayle

Péraldi-Roux

Gautheron

et al. 2021

Fundamemntal Clinical Pharma

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The hormone ghrelin is the endogenous agonist of the G protein-coupled receptor (GPCR) termed growth hormone secretagogue receptor (GHSR). Ghrelin inhibits glucose-stimulated insulin secretion by activating pancreatic GHSR. Recently, Liver-Expressed Antimicrobial Peptide 2 (LEAP2) was recognized as an endogenous GHSR ligand that blocks ghrelin-induced actions. Nonetheless, the effect of LEAP2 on glucose-stimulated insulin secretion from pancreatic islets is unknown. We aimed at exploring the activity of LEAP2 on glucose-stimulated insulin secretion. Islets of Langerhans isolated from rat pancreas were exposed to glucose in the presence or in the absence of LEAP2 and ghrelin and then insulin secretion was assayed. LEAP2 did not modulate glucose-stimulated insulin secretion. However, LEAP2 blocked the insulinostatic action of ghrelin. Our data show that LEAP2 behaves as an antagonist of pancreatic GHSR.

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The ups and downs of growth hormone secretagogue receptor signaling

Cited by 25 publications

References 153 publications

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

Liver‐Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets

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