Evaluation and Diagnostic Potential of Serum Ghrelin in Feline Hypersomatotropism and Diabetes Mellitus

BACKGROUND: Ghrelin is a growth hormone secretagogue. It is a potent regulator of energy homeostasis. Ghrelin concentration is down‐regulated in humans with hypersomatotropism (HS) and increases after successful treatment. Additionally, ghrelin secretion seems impaired in human diabetes mellitus (DM). HYPOTHESIS: Serum ghrelin concentration is down‐regulated in cats with HS‐induced DM (HSDM) compared to healthy control cats or cats with DM unrelated to HS and increases after radiotherapy. ANIMALS: Cats with DM (n = 20) and with HSDM (n = 32), 13 of which underwent radiotherapy (RT‐group); age‐matched controls (n = 20). METHODS: Retrospective cross‐sectional study. Analytical performance of a serum total ghrelin ELISA was assessed and validated for use in cats. Differences in serum ghrelin, fructosamine, IGF‐1 and insulin were evaluated. RESULTS: Ghrelin was significantly higher (P < .001) in control cats (mean ± SD: 12.9 ± 6.8 ng/mL) compared to HSDM‐ (7.9 ± 3.3 ng/mL) and DM‐cats (6.7 ± 2.3 ng/mL), although not different between the HSDM‐ and DM‐cats. After RT ghrelin increased significantly (P = .003) in HSDM‐cats undergoing RT (from 6.6 ± 1.9 ng/mL to 9.0 ± 2.2 ng/mL) and the after RT ghrelin concentrations of HSDM cats were no longer significantly different from the serum ghrelin concentration of control cats. Serum IGF‐1 did not significantly change in HSDM‐cats after RT, despite significant decreases in fructosamine and insulin dose. CONCLUSION AND CLINICAL IMPORTANCE: Ghrelin appears suppressed in cats with DM and HSDM, although increases after RT in HSDM, suggesting possible presence of a direct or indirect negative feedback system between growth hormone and ghrelin. Serum ghrelin might therefore represent a marker of treatment effect

Ghrelin axis genes, peptides and receptors : recent findings and future challenges

The ghrelin axis consists of the gene products of the ghrelin gene (GHRL), and their receptors, including the classical ghrelin receptor GHSR. While it is well-known that the ghrelin gene encodes the 28 amino acid ghrelin peptide hormone, it is now also clear that the locus encodes a range of other bioactive molecules, including novel peptides and non-coding RNAs. For many of these molecules, the physiological functions and cognate receptor(s) remain to be determined. Emerging research techniques, including proteogenomics, are likely to reveal further ghrelin axis-derived molecules. Studies of the role of ghrelin axis genes, peptides and receptors, therefore, promises to be a fruitful area of basic and clinical research in years to come

Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice

The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage

Ghrelin Decreases Firing Activity of Gonadotropin-Releasing Hormone (GnRH) Neurons in an Estrous Cycle and Endocannabinoid Signaling Dependent Manner.

The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+)-imaging revealed a ghrelin-triggered increase of the Ca(2+)-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca(2+)-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40nM-4μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner

Mouse circadian plasma leptin and active ghrelin rhythms under ad libitum and scheduled feeding

Thesis (M.S.) University of Alaska Fairbanks, 2007Light is the strongest timing cue for the circadian system, but non-photic cues can also entrain the master circadian clock, i.e., suprachiasmatic nuclei (SCN). In one of our mouse line (ENTR), all mice entrain to scheduled feeding, while in another (NON-ENTR) only 4 % entrain. In order to explore key physiological pathways involved in that process, I quantified the circadian rhythms of plasma leptin and active ghrelin of these two lines of mice under a 12:12 hour light-dark cycle with ad libitum feeding and six hours of food availability during the light period. Plasma active ghrelin induced opposite circadian rhythms compared to leptin, which were most pronounced under scheduled feeding when leptin was highest during and right after the food availability period; active ghrelin was highest at night when food was not available. Compared to ad libitum feeding, the overall concentration of leptin decreased and active ghrelin concentration increased significantly under scheduled feeding. The plasma active ghrelin circadian rhythms of ENTR mice were more robust with higher amplitude rhythms than the NON-ENTR mice under ad libitum feeding and scheduled feeding. I hypothesize that the high amplitude plasma active ghrelin circadian rhythm provides a signal for the ENTR mice to entrain to scheduled feedingIntroduction -- Materials and methods -- Animals under ad libitium feeding -- Animals under scheduled-feeding -- Procedure for obtaining blood samples -- Biochemical analysis -- Statistics -- Results -- Body weight -- Plasma leptin concentrations -- Plasma active ghrelin concentrations -- Behavioral entrainment to scheduled feeding -- Discussion --Circadian plasma leptin levels under different feeding conditions -- Circadian plasma ghrelin levels under different feeding conditions -- Relationship between circadian plasma leptin and active ghrelin levels after scheduled feeding -- Conclusions -- Literature cited

Attribution of ghrelin to cancer; Attempts to unravel an apparent controversy

Ghrelin is an endogenous peptide hormone mainly produced in the stomach. It has been known to regulate energy homeostasis, stimulate secretion of growth hormone, and mediate many other physiologic effects. Various effects attributed to ghrelin contribute to many aspects of cancer development and progression. Accordingly, a large body of evidence has emerged about the association of ghrelin with several types of cancer in scales of cell-line, animal, and human studies. However, existing data are controversial. This controversy occurs in two main domains: one is the controversial results in local effects of ghrelin on different types of human cancer cell-lines; the second is the apparent disagreement in the results o

The cumulative effects of seven days of imposed exercise on energy balance and appetite regulation

A thesis submitted to the University of Bedfordshire, in fulfilment of the requirements for the degree of MSc by ResearchIncreasing energy expenditure (EE) through regular exercise is a promising strategy to prevent body fat gain. However, imposed exercise interventions often produce weight loss that is less than theoretically expected, possibility due to compensatory mechanisms in energy intake (EI) and EE. Study one was designed to determine whether a combined written and photographic food diary was a reliable measure of EI within a free-living environment across seven days. The results suggested this method was reliable at the group level. However, 95% limits of agreement (LoA) showed large variability (-1258 to 1545 kcal/day) at the individual level. Study two investigated acylated ghrelin, PYY and energy balance in response to 7-days of imposed exercise and a control condition. EI increased by 511 kcal/day in the exercise condition (P=0.005). Late-postprandial acylated ghrelin concentrations were higher in the exercise condition (P=0.072), but did not change from pre- to post intervention. There was a larger, but non-significant, increase in EI at the postprandial ad libitum pasta meal in the exercise condition (P=0.285). In conclusion, 7-days exercise resulted in increased EI under free-living conditions; similar results were found when assessed in a controlled laboratory environment. A larger sample size would allow confirmation of the findings

Neuropeptide receptors as potential antiepileptic drug targets : focus on the ghrelin axis

Epilepsy is a very serious neurological disorder which is often underrepresented. Around 50 million individuals worldwide have active epilepsy with recurrent seizures and in spite of the medical advances over the years, 30% of these patients remain as drug resistant (Pati 2010). Even after several years of research, there is still a lack of good understanding on the pathophysiology of seizure disorders (Perucca 2011). Investigators in this field believe that there is a great need for novel antiepileptic drugs (AEDs) that act differently than the drugs available on the market. The majority of AEDs act by blocking sodium channels (phenytoin, carbamazepine) or by the augment of GABAergic transmission (phenobarbital, valproic acid). A newer generation of AEDs has expanded therapeutic options, however these are not superior to the older drugs (Hitiris 2006). Patients with mesial temporal lobe epilepsy (mTLE) are among the most pharmacoresistant to these medications (Pati 2010). In order to attempt the rectification of this dilemma, the neuropharmacologist needs to not only try and find AEDs with new mechanisms of action, but to also keep in mind what information is currently available on the pathophysiology of epilepsy. It is clear that during the complicated process of epileptogenesis, several different mechanisms are taking place, thus one should ideally identify new compounds that are capable of targeting different pathways simultaneously. The focus of epilepsy researchers is to identify compounds that are not only capable of attenuating seizures (anticonvulsant), but are also antiepileptogenic (can prevent epilepsy) or disease-modifying (halting its progression).peer-reviewe