Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

Stevanović, Darko; Grefhorst, Aldo; Themmen, Axel P. N.; Popović, Vera; Holstege, Jan C.; Haasdijk, Elize D.; Trajkovič, Vladimir; Lely, Aart Jan van der; Delhanty, Patric J. D.

doi:10.1371/journal.pone.0098180

Cited by 36 publications

(22 citation statements)

References 47 publications

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“…Future studies testing whether the putative DAG receptor and GHSR are co-localised at the ARC are critical for discriminating between these possibilities. The induction of c-Fos has been previously used to identify the neuronal targets of DAG (33,47). Two independent studies have shown that DAG increases c-Fos in the POMC or nesfatin-1 neurones of the ARC.…”

Section: Discussionmentioning

confidence: 99%

Des‐Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin‐Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin

Fernández

Cabral

Cornejo

et al. 2016

J Neuroendocrinology

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Ghrelin is a stomach-derived octanoylated peptide hormone that plays a variety of well-established biological roles acting via its specific receptor known as growth hormone secretagogue receptor (GHSR). In plasma, a des-octanoylated form of ghrelin, named des-acyl ghrelin (DAG), also exists. DAG is suggested to be a signalling molecule that has specific targets, including the brain, and regulates some physiological functions. However, no specific receptor for DAG has been reported until now, and, consequently, the potential role of DAG as a hormone has remained a matter of debate. In the present study, we show that DAG specifically binds to and acts on a subset of arcuate nucleus (ARC) cells in a GHSR-independent manner. ARC cells labelled by a DAG fluorescent tracer include the neuropeptide Y (NPY) and non-NPY neurones. Given the well-established role of the ARC in appetite regulation, we tested the effect of centrally administered DAG on food intake. We found that DAG failed to affect dark phase feeding, as well as food intake, after a starvation period; however, it impaired the orexigenic actions of peripherally administered ghrelin. Thus, we conclude that DAG directly targets ARC neurones and antagonises the orexigenic effects of peripherally administered ghrelin.

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Section: Discussionmentioning

confidence: 99%

Des‐Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin‐Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin

Fernández

Cabral

Cornejo

et al. 2016

J Neuroendocrinology

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“…There are two major molecular forms of ghrelin, acylated ghrelin and des‐acyl ghrelin. Recently it has been suggested that des‐acyl ghrelin counteracts the orexigenic effects of acylated ghrelin (Stevanovic et al, 2014). Ghrelin levels usually increase in response to fasting.…”

Section: Discussionmentioning

confidence: 99%

Short term exendin‐4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams

Chan

Saad

Simar

et al. 2015

Intl J of Devlp Neuroscience

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Abbreviations AGRP: Agouti-related protein; ATGL: adipocyte triglyceride lipase; ARC: arcuate nucleus; AZGP1: α(2)-zinc-glycoprotein 1; CPT-1: carnitine palmitoyltransferase-1; Ex-4: exendin-4; FASN: fatty acid synthase;FOXO1: Forkhead box protein O 1; GLP-1: glucagon-like peptide-1; HFD: high-fat diet; IUGR: intrauterine growth restriction; MC4R: melanocortin 4 receptor; NPY: neuropeptide Y ; NPY Y1R: Neuropeptide Y1 receptor; Ob-Rb: active lepton receptor; P: postnatal day; POMC: pro-opiomelanocortin; PGC1α: peroxisome proliferator activated receptor gamma coactivator 1α; PPARγ: peroxisome proliferator-activated receptor γ; SREBP: sterol regulatory element binding protein.; SOCS: suppressor of cytokine-signaling; STAT: signal transducer and activator of transcription. administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect lapsed upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling in a rodent model can reverse transmitted metabolic disorders due to maternal obesity. Methods:Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.Results: Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue. Conclusion:Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease.

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“…Similarly, another study [8] found that the increase in UAG during an exercise training program was associated with reduced body weight without reducing calorie intake. This prompted us to speculate that UnAG might induce body weight loss by regulating neuronal activity [52] in the hypothalamus and brainstem which controls energy homeostasis and body weight [50]. Yet, further investigation is required to examine this speculation.…”

Section: Unacylated Ghrelin Restored Impaired Insulin Signaling In DImentioning

confidence: 99%

Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice

Tam

Pei

Yung

et al. 2015

Pflugers Arch - Eur J Physiol

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Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.

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Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

Cited by 36 publications

References 47 publications

Des‐Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin‐Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin

Des‐Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin‐Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin

Short term exendin‐4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams

Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice

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