Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve

Davis, Elizabeth A.; Wald, Hallie S.; Suarez, Andrea N.; Zubcevic, Jasenka; Liu, Clarissa M.; Cortella, Alyssa M.; Kamitakahara, Anna; Polson, Jaimie W.; Arnold, Myrtha; Grill, Harvey J.; Lartigue, Guillaume de; Kanoski, Scott E.

doi:10.1016/j.cub.2020.08.069

Cited by 55 publications

(60 citation statements)

References 46 publications

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“…GHSR antagonist microinjection into the ventral tegmental area in the midbrain blocks the orexigenic effect of peripherally administered ghrelin [ 60 ]. Using RNA interference methodology, vagal afferent neuron-selective GHSR knock-down increases meal frequency without effects on cumulative food intake or refeeding following an unanticipated fast [ 61 ]. Interestingly, separate studies have alternatively demonstrated that peri-vagal capsaicin treatment and/or surgical subdiaphragmatic vagotomy block food intake [ 62 ] vs do not affect the actions of administered acyl-ghrelin to increase food intake [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions

Gupta

Patterson

Osborne-Lawrence

et al. 2021

Molecular Metabolism

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Objective Acyl-ghrelin regulates eating, body weight, blood glucose, and GH secretion upon binding to its receptor GHSR (growth hormone secretagogue receptor; ghrelin receptor). GHSR is distributed in several brain regions and some peripheral cell-types including pituitary somatotrophs. The objective of the current study was to determine the functional significance of acyl-ghrelin's action on GHSR-expressing somatotrophs in mediating GH secretion and several of acyl-ghrelin's metabolic actions. Methods GH-IRES-Cre mice and loxP-flanked (floxed) GHSR mice were newly developed and then crossed to one another to generate mice that lacked GHSR selectively from somatotrophs. Following validation of mice with somatotroph-selective GHSR deletion, metabolic responses of these mice and control littermates were assessed following both acute and chronic acyl-ghrelin administration, a 24-h fast, and a prolonged 60% chronic caloric restriction protocol modeling starvation. Results In mice with somatotroph-selective GHSR deletion, a single peripheral injection of acyl-ghrelin failed to induce GH secretion or increase food intake, unlike wild-type and other littermate control groups. However, the usual acute blood glucose increase in response to the acyl-ghrelin bolus was preserved. Similarly, chronic s.c. acyl-ghrelin administration to mice with somatotroph-selective GHSR deletion failed to increase plasma GH, food intake, or body weight. Physiologically elevating plasma acyl-ghrelin via a 24-h fast also failed to raise plasma GH and resulted in a limited hyperphagic response upon food reintroduction in mice with somatotroph-selective GHSR deletion, although those mice nonetheless did not exhibit an exaggerated reduction in blood glucose. Physiologically elevating plasma acyl-ghrelin via a 15-day caloric restriction protocol which provided only 40% of usual daily calories failed to raise plasma GH in mice with somatotroph-selective GHSR deletion, although those mice did not exhibit life-threatening hypoglycemia. Conclusions These results reveal that direct engagement of GHSR-expressing somatotrophs is required for a peripheral ghrelin bolus to acutely stimulate GH secretion and the actions of chronic acyl-ghrelin delivery and physiological plasma acyl-ghrelin elevations to increase plasma GH. These results also suggest that actions of acyl-ghrelin to increase food intake and body weight are reliant on direct activation of GHSRs expressed on somatotrophs. Furthermore, these results suggest that the glucoregulatory actions of acyl-ghrelin – in particular, its actions to raise blood glucose when acutely administered, prevent small blood glucose drops following a 24-h fast, and avert life-threatening hypoglycemia during an acute-on-chronic caloric restriction protocol – do not depend on GHSR expression by somatotrophs.

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Section: Discussionmentioning

confidence: 99%

Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions

Gupta

Patterson

Osborne-Lawrence

et al. 2021

Molecular Metabolism

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“…Additionally, ghrelin can interact with the VN for regulation of feeding behaviour and metabolism [ 62 ]. Rats with ghrelin receptor knockdown on the vagal afferent nerve displayed metabolic disturbances, meal pattern disruption, and hippocampal-dependant memory impairment [ 63 ].…”

Section: Ghrelin and The Ghrelin Receptormentioning

confidence: 99%

Gut peptides and the microbiome: focus on ghrelin

Leeuwendaal

Cryan²,

Schellekens

2021

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review In this review, we present recent insights into the role of the gut microbiota on gastrointestinal (GI) peptide secretion and signalling, with a focus on the orexigenic hormone, ghrelin. Recent findings Evidence is accumulating suggesting that secretion of GI peptides is modulated by commensal bacteria present in our GI tract. Recent data shows that the gut microbiome impacts on ghrelinergic signalling through its metabolites, at the level of the ghrelin receptor (growth hormone secretagogue receptor) and highlights concomitant changes in circulating ghrelin levels with specific gut microbiota changes. However, the mechanisms by which the gut microbiota interacts with gut peptide secretion and signalling, including ghrelin, are still largely unknown. Summary The gut microbiota may directly or indirectly influence secretion of the orexigenic hormone, ghrelin, similar to the modulation of satiety inducing GI hormones. Although data demonstrating a role of the microbiota on ghrelinergic signalling is starting to emerge, future mechanistic studies are needed to understand the full impact of the microbiota-ghrelin axis on metabolism and central-regulated homeostatic and non-homeostatic controls of food intake.

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“…In support of this hypothesis, for example, a recent functional analysis using RNAinterference to knockdown GHSR revealed that GHSR1a of gutinnervating vagal afferent neurons is necessary for ghrelin signaling in rat. Also, GHSR expression in the nodose ganglion is reduced with targeted RNA-interference [34].…”

Section: Ghrelin Orexigenic Agentmentioning

confidence: 99%

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

Nagi

Habib

2021

Cellular Signalling

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Obesity is a global burden and a chronic ailment with damaging overall health effects. Ghrelin, an octanoylated 28 amino acid peptide hormone, is secreted from the oxyntic mucosa of the stomach. Ghrelin acts on regions of the hypothalamus to regulate feeding behavior and glucose homeostasis through its G protein-coupled receptor. Recently, several central pathways modulating the metabolic actions of ghrelin have been reported. While these signaling pathways can be inhibited or activated by antagonists or agonists, they can also be discriminatingly activated in a "biased" response to impart different degrees of activation in distinct pathways downstream of the receptor. Here, we review recent ghrelin biased signaling findings as well as characteristics of ghrelin hormone and its receptors pertinent for biased signaling. We then evaluate the feasibility for ghrelin receptor biased signaling as a strategy for the development of effective pharmacotherapy in obesity treatment.

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Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve

Cited by 55 publications

References 46 publications

Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions

Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions

Gut peptides and the microbiome: focus on ghrelin

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

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