Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement

The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([d-Lys3]-growth hormone-releasing peptide-6 and JMV-2959) at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the midlight phase, suggesting that pharmacological activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, whereas blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

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Intraportal Infusion of Ghrelin Could Inhibit Glucose-Stimulated GLP-1 Secretion by Enteric Neural Net in Wistar Rat

BioMed Research International ◽

10.1155/2014/923564 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Xiyao Zhang ◽

Wensong Li ◽

Ping Li ◽

Manli Chang ◽

Xu Huang ◽

...

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Portal Vein ◽

Wistar Rat ◽

Inhibitory Effect ◽

Neural Net ◽

Incretin Effect ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Intraportal Infusion

As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect.

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Assessing the role of the growth hormone secretagogue receptor in motivational learning and food intake.

Behavioral Neuroscience ◽

10.1037/a0016808 ◽

2009 ◽

Vol 123 (5) ◽

pp. 1058-1065 ◽

Cited By ~ 11

Author(s):

Alexander W. Johnson ◽

Rebecca Canter ◽

Michela Gallagher ◽

Peter C. Holland

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue

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LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

Frontiers in Endocrinology ◽

10.3389/fendo.2021.717544 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xuehan Lu ◽

Lili Huang ◽

Zhengxiang Huang ◽

Dandan Feng ◽

Richard J. Clark ◽

...

Keyword(s):

Growth Hormone ◽

Energy Balance ◽

Food Intake ◽

Antimicrobial Peptide ◽

Molar Ratio ◽

Positive Energy ◽

Energy Status ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.

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Effect of chronic hyperghrelinemia on ingestive action of ghrelin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00331.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. R803-R808 ◽

Cited By ~ 21

Author(s):

Wei Wei ◽

Xiang Qi ◽

Jason Reed ◽

Jeff Ceci ◽

Hui-Qun Wang ◽

...

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Transgenic Mice ◽

Growth Response ◽

Fat Pad ◽

Endogenous Ligand ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Gh Secretion ◽

Ghrelin Gene

The stomach hormone ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Systemic administration of ghrelin will cause elevations in growth hormone (GH) secretion, food intake, adiposity, and body growth. Ghrelin also affects insulin secretion, gastric acid secretion, and gastric motility. Several reports indicate that repeated or continuous activation of GHS-R by exogenous GHSs or ghrelin results in a diminished GH secretory response. The purpose of this study was to examine the extent to which the acute stimulation of food intake by exogenous ghrelin is altered by chronic hyperghrelinemia in transgenic mice that overexpress the human ghrelin gene. The present findings show that the orexigenic action of exogenous ghrelin is not diminished by a chronic hyperghrelinemia and indicate that the food ingestive pathway of the GHS-R is not susceptible to desensitization. In contrast, the epididymal fat pad growth response, like the GH response, to exogenous ghrelin is blunted in ghrelin transgenic mice with chronic hyperghrelinemia.

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Recent Advances in Potential Clinical Application of Ghrelin in Obesity

Journal of Obesity ◽

10.1155/2012/535624 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Christine Delporte

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Biological Effects ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Taste Receptor ◽

Molecular Targets ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Amino Acid Peptide

Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelinO-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets.

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Evidence Supporting a Role for Constitutive Ghrelin Receptor Signaling in Fasting-Induced Hyperphagia in Male Mice

Endocrinology ◽

10.1210/en.2017-03101 ◽

2017 ◽

Vol 159 (2) ◽

pp. 1021-1034 ◽

Cited By ~ 25

Author(s):

Gimena Fernandez ◽

Agustina Cabral ◽

María F Andreoli ◽

Alexandra Labarthe ◽

Céline M'Kadmi ◽

...

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Peptide Hormone ◽

Negative Energy ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor ◽

Orexigenic Peptide ◽

Hypothalamic Arcuate Nucleus

Abstract Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein–coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone–releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance.

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