The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin’s biological interactions and avenues for controlling ghrelin signaling

Cleverdon, Elizabeth R.; McGovern-Gooch, Kayleigh R.; Hougland, James L.

doi:10.1080/09687688.2017.1388930

Cited by 13 publications

(12 citation statements)

References 142 publications

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“…However, we cannot rule out in this study that there is not breakdown to DAG that could contribute to the levels of 125 I-ghrelin measured in brain. AG breakdown to DAG can be done by numerous circulating esterases, including butylcholinesterase and carboxypeptidase, and it is possible for various esterases to compensate when one is lacking [50]. However, what contributes to the further breakdown of DAG in brain is not known.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

Rhea

Salameh

Gray

et al. 2018

Molecular Metabolism

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ObjectiveThe blood–brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain.MethodsWe utilized the sensitive and quantitative multiple-time regression analysis technique to determine the transport rate of mouse and human acyl ghrelin (AG) and desacyl ghrelin (DAG) in wildtype and Ghsr null mice. We also measured the regional distribution of these ghrelin peptides throughout the brain. Lastly, we characterized the transport characteristics of human DAG by measuring the stability in serum and brain, saturability of transport, and the complete transfer across the brain endothelial cell.ResultsWe found the transport rate across the BBB of both forms of ghrelin, AG, and DAG, were not affected by the loss of GHSR. We did find differences in the transport rate between the two isoforms, with DAG being faster than AG; this was dependent on the species of ghrelin, human being faster than mouse. Lastly, based on the ubiquitous properties of ghrelin throughout the CNS, we looked at regional distribution of ghrelin uptake and found the highest levels of uptake in the olfactory bulb.ConclusionsThe data presented here suggest that ghrelin transport can occur independently of the GHSR, and ghrelin uptake varies regionally throughout the brain. These findings better our understanding of the gut-brain communication and may lead to new understandings of ghrelin physiology.

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Section: Discussionmentioning

confidence: 99%

Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

Rhea

Salameh

Gray

et al. 2018

Molecular Metabolism

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“…Once secreted, acyl-ghrelin binds to GHS-R1a in multiple central and peripheral targets to modulate energy homeostasis, reproduction, cognition, reward and emotion [50,51]. These targets include most peripheral tissues and endocrine glands like the pituitary gland, pancreas, liver, adrenal glands, reproductive tissues, immune cells, skeletal and muscle cells, and brain [52,53]. It is not clear whether acyl-ghrelin from the periphery can actually reach the brain to reach all regions expressing GHS-R1a.…”

Section: Ghs-r1a Signaling Mechanismsmentioning

confidence: 99%

Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity

Abizaid

Hougland

2020

Trends in Endocrinology & Metabolism

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Ghrelin and the growth hormone secretagogue receptor 1a (GHS-R1a) are important targets for disorders related to energy balance and metabolic regulation. Pharmacological control of ghrelin signaling is a promising avenue to address health issues involving appetite, weight gain, obesity, and related metabolic disorders, and may be an option for patients suffering from wasting conditions like cachexia. In this review, we summarize recent developments in the biochemistry of ghrelin and GHS-R1a signaling. These include unravelling the enzymatic transformations that generate active ghrelin and the discovery of multiple proteins that interact with ghrelin and GHS-R1a to regulate signaling. Furthermore, we propose that harnessing these processes will lead to highly selective treatments to address obesity, diabetes, and other metabolism-linked disorders.

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“…Ghrelin is the only protein known to be octanoylated, which means that inhibiting GOAT is unlikely to have side effects owing to interference with other acylating enzymes . As such, modulation of ghrelin signalling through GOAT inhibition presents a potential therapeutic avenue for treating obesity and T2DM . Structure‐activity analyses of ghrelin binding to GOAT have facilitated the development and optimization of GOAT inhibitors .…”

Section: Resultsmentioning

confidence: 99%

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

et al. 2019

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Summary In early childhood, individuals with Prader‐Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: “PWS” AND “therapy” OR “[drug name]”; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long‐term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off.

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The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin’s biological interactions and avenues for controlling ghrelin signaling

Cited by 13 publications

References 142 publications

Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

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