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

Rhea, Elizabeth M.; Salameh, Therese S.; Gray, Sarah M.; Niu, Jingjing; Banks, William A.; Tong, Jenny

doi:10.1016/j.molmet.2018.09.007

Cited by 76 publications

(52 citation statements)

References 52 publications

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“…On one hand, although only acyl ghrelin is able to activate GHSR, 66–94% of circulating ghrelin is actually found in the des-acyl form [55], [56], [57], due to the activity of esterases and APT-1 [49]. In addition, ghrelin has a limited capacity to cross the blood-brain-barrier [58]. On the other hand, Dln101 emerges as a relevant candidate to maintain GHSR activation due to its increased stability in the acylated residue.…”

Section: Discussionmentioning

confidence: 99%

Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity

Stutz¹,

Nasrallah

Nigro³

et al. 2019

Molecular Metabolism

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Objective Dopamine neurons in the Substantia nigra ( SN ) play crucial roles in control of voluntary movement. Extensive degeneration of this neuronal population is the cause of Parkinson's disease (PD). Many factors have been linked to SN DA neuronal survival, including neuronal pacemaker activity (responsible for maintaining basal firing and DA tone) and mitochondrial function. Dln-101, a naturally occurring splice variant of the human ghrelin gene, targets the ghrelin receptor (GHSR) present in the SN DA cells . Ghrelin activation of GHSR has been shown to protect SN DA neurons against 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. We decided to compare the actions of Dln-101 with ghrelin and identify the mechanisms associated with neuronal survival. Methods Histologial, biochemical, and behavioral parameters were used to evaluate neuroprotection. Inflammation and redox balance of SN DA cells were evaluated using histologial and real-time PCR analysis. Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology was used to modulate SN DA neuron electrical activity and associated survival. Mitochondrial dynamics in SN DA cells was evaluated using electron microscopy data. Results Here, we report that the human isoform displays an equivalent neuroprotective factor. However, while exogenous administration of mouse ghrelin electrically activates SN DA neurons increasing dopamine output, as well as locomotion, the human isoform significantly suppressed dopamine output, with an associated decrease in animal motor behavior. Investigating the mechanisms by which GHSR mediates neuroprotection, we found that dopamine cell-selective control of electrical activity is neither sufficient nor necessary to promote SN DA neuron survival, including that associated with GHSR activation. We found that Dln101 pre-treatment diminished MPTP-induced mitochondrial aberrations in SN DA neurons and that the effect of Dln101 to protect dopamine cells was dependent on mitofusin 2, a protein involved in the process of mitochondrial fusion and tethering of the mitochondria to the endoplasmic reticulum. Conclusions Taken together, these observations unmasked a complex role of GHSR in dopamine neuronal protection independent on electric activity of these cells and revealed a crucial role for mitochondrial dynamics in some aspects of this process.

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Section: Discussionmentioning

confidence: 99%

Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity

Stutz¹,

Nasrallah

Nigro³

et al. 2019

Molecular Metabolism

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“…A further study showed that the highest uptake of systemically injected 131 I‐ghrelin occurs in the occipital cortex, olfactory bulb and hypothalamus, in that order, and that ghrelin uptake in the hippocampus is similar to the uptake in the whole brain . Further studies showed that the transport of human 131 I‐ghrelin into the brain is affected by the physiological status, being decreased in obese mice and promoted by hypertriglyceridaemia, independent of the presence of GHSR . Another study showed that 131 I‐ghrelin interacts with RBE4 cerebral microvessel endothelial cells .…”

Section: Potential Mechanisms Transporting Plasma Ghrelin Into the Brainmentioning

confidence: 93%

Brain accessibility delineates the central effects of circulating ghrelin

Perelló

Cabral

Cornejo

et al. 2019

J Neuroendocrinology

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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.

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“…These findings suggest that, similar to other islet and gastrointestinal hormones, acyl ghrelin may act centrally to regulate insulin levels and glucose metabolism. This is supported by observations that a small amount of acyl and DAG can cross the blood‐brain barrier to reach the central nervous system …”

Section: Ghrelin Regulation Of Insulin Secretion: the Role Of The Cenmentioning

confidence: 66%

Ghrelin regulation of glucose metabolism

Gray

Page

Tong

2019

J Neuroendocrinology

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| INTRODUC TI ONSubsequent to its discovery in 1999, 1 ghrelin has been increasingly recognised for its role in diverse biological functions. Ghrelin stimulates growth hormone and adrenocorticotrophic hormone secretion, increases appetite and nutrient intake, decreases mean arterial blood pressure and augments cardiac output, enhances gut motility and gastric acid secretion, influences energy expenditure, affects learning and memory, and contributes to the hedonic aspects of food. 2,3 Ghrelin also impacts glucose metabolism both during typical fasting and fed states and at times of stress. For example, during starvation, ghrelin is essential for maintaining glucose homeostasis. 4-7 Although the ability of ghrelin to regulate glucose metabolism is widely accepted, the mechanisms by which it achieves these effects remain to be fully clarified. Ghrelin-induced lipolysis and counter regulatory hormone release is well recognised, 8-10 although only recently has its modulation of insulin release via pancreatic islet δ-cells 11,12 and a role in stimulating the secretion of other gastrointestinal hormones been identified. 10,13 This review focuses on the effects of ghrelin on glucose metabolism by summarising in vitro, rodent and human studies, at the same time as highlighting recent discoveries (Figure 1). Throughout the review, we use "acyl ghrelin" and "ghrelin" interchangeably and explicitly state studies reporting desacyl ghrelin or total ghrelin findings. Funding informationNational Institute of Diabetes and Digestive and Kidney Diseases: T32DK007012 to S.M.G., R01DK097550 to J.T Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate. K E Y W O R D Sghrelin, glucose tolerance, insulin, insulin secretion

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

Cited by 76 publications

References 52 publications

Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity

Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity

Brain accessibility delineates the central effects of circulating ghrelin

Ghrelin regulation of glucose metabolism

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