Unacylated Ghrelin Research Articles

Experimental ghrelin administration affects migratory behaviour in a songbird

Twice a year, billions of birds take on drastic physiological and behavioural changes to migrate between breeding and wintering areas. On migration, most passerine birds regularly stop over along the way to rest and refuel. Endogenous energy stores are not only the indispensable fuel to complete long distance flights, but are also important peripheral signals that once integrated in the brain modulate crucial behavioural decisions, such as the decision to resume migration after a stopover. A network of hormones signals metabolic fuel availability to the brain in vertebrates, including the recently discovered gut-hormone ghrelin. Here, we show that ghrelin takes part in the control of migratory behaviour during spring migration in a wild migratory passerine. We manipulated blood concentrations of ghrelin of 53 yellow-rumped warblers (Setophaga coronata coronata) caught during stopover and automatically radio-tracked their migratory behaviour following release. We found that injections of acylated and unacylated ghrelin rapidly induced movements away from the release site, indicating that the ghrelin system acts centrally to mediate stopover departure decisions. The effects of the hormone manipulation declined within 8 h following release, and did not affect the overall rate of migration. These results provide experimental evidence for a pivotal role of ghrelin in the modulation of behavioural decisions during migration. In addition, this study offers insights into the regulatory functions of metabolic hormones in the dialogue between gut and brain in birds.

Transgenic unacylated ghrelin overexpression modulates adipocyte actin cytoskeleton remodelling and expansion in high-fat diet induced obesity in mice

Rationale: Adipose tissue is key player in the development of obesity and obesity-related complications. Recent evidence shows that adipocyte size regulation through actin cytoskeleton remodeling is mechanistically interlinked with disrupted cell metabolism, including reduced mitochondrial function and insulin signaling. The unacylated form of the hormone ghrelin (UnAG) is a novel profound metabolic modulator, with whole-body and tissue-specific effects. In rodent models it improves obesity-induced skeletal muscle insulin resistance, however its impact on adipocyte expansion and metabolism is currently unknown.

Effect of unacylated ghrelin on peripheral nerve regeneration.

Ghrelin is a circulating peptide hormone released by enteroendocrine cells of the gastrointestinal tract as two forms, acylated and unacylated. Acylated ghrelin (AG) binds to the growth hormone secretagogue receptor 1a (GHSR1a), thus stimulating food intake, growth hormone release, and gastrointestinal motility. Conversely, unacylated GHR (UnAG), through binding to a yet unidentified receptor, protects the skeletal muscle from atrophy, stimulates muscle regeneration, and protects cardiomyocytes from ischemic damage. Recently, interest about ghrelin has raised also among neuroscientists because of its effect on the nervous system, especially the stimulation of neurogenesis in spinal cord, brain stem, and hippocampus. However, few information is still available about its effectiveness on peripheral nerve regeneration. To partially fill this gap, the aim of this study was to assess the effect of UnAG on peripheral nerve regeneration after median nerve crush injury and after nerve transection immediately repaired by means of an end-to-end suture. To this end, we exploited FVB1 Myh6/Ghrl transgenic mice in which overexpression of the ghrelin gene (Ghrl) results in selective up-regulation of circulating UnAG levels, but not of AG. Regeneration was assessed by both functional evaluation (grasping test) and morphometrical analysis of regenerated myelinated axons. Results obtained lead to conclude that UnAG could have a role in development of peripheral nerves and during more severe lesions.

The impact of growth hormone replacement therapy on adipokines, but not upon Ghrelin.

Besides growth acceleration, growth hormone (GH) therapy of GH deficient (GHD) children improves body composition by decreasing body fat. This effect is due to GH interaction with lipid and carbohydrate metabolism, possibly also mediated by adipokines secreted by adipose tissue, and ghrelin. This study aimed to assess the impact of oneyear GH replacement therapy on the metabolic profile, adipokines, and acylated/ unacylated ghrelin of prepubertal children with GHD. Prospective observational study of 42 non-obese, prepubertal children with GHD followed up for twelve months. Mean lipid, carbohydrate, adipokine profiles, acylated/unacylated ghrelin, and body composition data before therapy onset were compared with measurements obtained after 6 and 12 months of GH therapy. Total body fat content and body fat percentage decreased significantly, while the lipid profile improved over the study period in the 42 GHD children with a mean age of 9.2 ±2.6 years. The levels of leptin and unacylated ghrelin decreased significantly, whereas adiponectin and acylated ghrelin values increased after GH therapy. In regression analysis models, GH treatment (reflected by increased absolute values or standard deviations of IGF1) influences the variation of leptin and adiponectin, but not ghrelin, independently of body composition - lean or fat mass. GH replacement therapy improves body composition, lipid, and adipokine profile in GHD children. Also, GH replacement therapy directly impacts leptin and adiponectin concentrations, independently of body composition. Further research is needed to identify the molecular mechanisms and metabolic pathways by which the GH/IGF1 axis influences adipokines secretion.

Overweight and obesity in type 1 diabetes is not associated with higher ghrelin concentrations

BackgroundSeveral studies have demonstrated suppressed levels of acylated (AG) and unacylated ghrelin (UAG) in patients with type 2 diabetes. However, the role of these hormones in type 1 diabetes has not been extensively studied. This study assessed the relationship between AG and UAG levels and body composition in patients with type 1 diabetes.MethodsWe selected eighteen patients with type 1 diabetes and divided them into two groups: non-obese (BMI < 25 kg/m2) and overweight (BMI ≥ 25 kg/m2). Demographics, parameters of body composition and serum parameters including AG and UAG, were assessed.ResultsThe patients with a BMI ≥ 25 kg/m2 were older and had a longer duration of diabetes. AG and UAG levels were not significantly different between non-obese and overweight groups (mean AG non-obese ± SD: 44.5 ± 29.4 pg/ml and mean UAG non-obese 42.4 ± 20.7 pg/ml vs mean AG overweight ± SD: 46.1 ± 29.6 pg/ml and mean UAG overweight 47.2 ± 18.2 pg/ml). AG/UAG ratios did not discriminate between these groups. There was a positive association of insuline dose/kg bodyweight with BMI (r2 = 0.45, p = 0.002).ConclusionsSurprisingly, unlike non-diabetics and in T2D, we did not observe a difference in plasma levels of AG and UAG between normal weight and overweight adult type 1 diabetics. However, we did observe a positive correlation between BMI and insuline dose/kg bodyweight, suggesting that exogenous insulin is more important than the ghrelin system in the development of obesity in type 1 diabetes.

Is ghrelin a biomarker of early-onset scoliosis in children with Prader\u2013Willi syndrome?

BackgroundAdolescents with idiopathic scoliosis display high ghrelin levels. As hyperghrelinemia is found in patients with PWS and early-onset scoliosis (EOS) is highly prevalent in these patients, our aims were to explore (1) whether ghrelin levels differ between those with and without EOS and correlate with scoliosis severity, and (2) whether ghrelin levels in the first year of life are associated with the later development of EOS.MethodsWe used a case control study design for the first question and a longitudinal design for the second. Patients with PWS having plasma ghrelin measurements recorded between 2013 and 2018 in our database were selected and 30 children < 10 years old with EOS and 30 age- and BMI-matched controls without EOS were included. The Cobb angle at diagnosis was recorded. In addition, 37 infants with a ghrelin measurement in the first year of life were followed until 4 years of age and assessed for EOS. Total ghrelin (TG), acylated (AG) and unacylated ghrelin (UAG), and the AG/UAG ratio were analyzed.ResultsEOS children had an AG/UAG ratio statistically significantly lower than controls. The Cobb angle was positively correlated with TG and UAG. TG and AG in the first year of life were higher in infants who later develop EOS without reaching a statistically significant difference.ConclusionsOur results suggest that ghrelin may play a role in the pathophysiology of EOS in PWS. Higher ghrelinemia in the first year of life required careful follow-up for EOS.

The Relationship of Serum Leptin and Ghrelin Levels with Craving and Withdrawal in Opioid Use Disorder.

This study aims to investigate plasma levels of leptin, acyl ghrelin, and unacylated ghrelin during heroin withdrawal in patients with opioid use disorder (OUD) with regard to the relationship of these levels with craving and their changes over time. This study included 28 male patients diagnosed with OUD according to DSM-5 diagnostic criteria who received inpatient rehabilitation. The control group included 28 healthy male volunteers with characteristics similar to the patient group. Plasma leptin, acyl ghrelin, and unacylated ghrelin levels of the patients were measured 3 times throughout the study by collecting blood on the first day, the seventh day at the end of the detox, and the twenty-first day. Blood was collected only once from the control group to determine their plasma leptin, acyl ghrelin, and unacylated ghrelin levels. Our study did not determine any statistically significant differences between patients with OUD and healthy controls with regard to plasma leptin, acyl ghrelin, and unacylated ghrelin levels on the first, seventh, and twenty-first days of withdrawal. Plasma levels of leptin, acyl ghrelin, and unacylated ghrelin did not significantly correlate with craving scores. This study does not support the hypothesis that plasma leptin, acyl ghrelin, and unacylated ghrelin levels are markers in those with OUD. Further research, particularly in humans, is recommended to replicate and expand on the findings of the current literature.

UNACYLATED GHRELIN PLASMA LEVELS ARE LOWER AND PREDICT 5-YEAR LOW MUSCLE MASS IN ELDERLY OBESE SUBJECTS

Aging-associated skeletal muscle loss may be paralleled by increased fat mass, both contributing to frailty and related healthcare and social costs. In general population cohorts, unacylated ghrelin (UnAG) plasma levels, an emerging modulator of skeletal muscle metabolism with potential muscle-anabolic actions, decrease in overweight-obese subjects [body mass index (BMI)> 25 kg/m2]. Potential associations between UnAG, overweight-obesity and muscle mass (MM) in elderly humans are currently unknown. In 450 elderly individuals (age>65y; M/F: 179/271) from the North-East Italy MoMa population study we investigated potential associations between ghrelin profile [total (TG), acylated (AG) and unacylated hormone (UnAG)] and body mass index (BMI). MM index (MM/m2) was measured in 133 subjects (M/F: 72/81) by bioelectrical impedance analysis after 5 years. Low MM-index cut-off was defined as two standard deviation lower than average MM-index in young (18-39) reference subjects from the same population. In elderly subjects, UnAG was lower (p<0.01) in overweight-obese compared to lean. Multiple regression analysis showed that UnAG was associated (P<0.01) with BMI independently of potential confounders such as gender, metabolic and inflammatory markers. In logistic regression analysis, lower basal UnAG predicted (p<0.05) low MM-index independently of gender, BMI and metabolic confounders. In elderly subjects from a North-East Italy general population cohort, unacylated ghrelin levels are lower in overweight-obese individuals and predict 5-year muscle mass independently from BMI. The present results suggest that lower UnAG may contribute to lower muscle mass in obese elderly individuals.

Exogenous acylated ghrelin promotes but un-acylated ghrelin prevents hepatic steatosis by modulating peripheral insulin resistance and hepatic oxidative and endoplasmic reticulum stress

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.

Unacylated ghrelin ameliorates muscle atrophy and contractile dysfunction in age‐associated loss of muscle mass and function

Sarcopenia, the progressive loss of muscle mass and dysfunction, universally affects the elderly and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation (acyl ghrelin, AG), which binds to its receptors (GHSR1a) in the brain. Growing studies demonstrate that AG and “unacyl” ghrelin (UnAG) both have direct impacts on proliferation independent of GHSR1a. Neuronal precursor cells and myoblast incubated with UnAG increases proliferation and protein synthesis rate by promoting differentiation and fusion. Thus, we hypothesized that UnAG ameliorates neurogenic atrophy and contractile dysfunction in aged skeletal muscle. Young (4 mo.) and old (18 mo.) female mice were treated with saline or UnAG. UnAG (100 µg/kg/day) via osmotic pump for 9-10 months. We assessed in vitro contractile properties of isolated extensor digitorum longus (EDL). UnAG treatment significantly increased terminal serum UnAG levels in the old animals. In contrast to previous studies using AG, UnAG did not affect food consumption or body weight. Muscle mass of gastrocnemius and quadriceps were ~20-30% decreased in old mice, but UnAG ameliorated the atrophy by 15-30% for both muscles. Specific force (force per cross-sectional are) of isolated EDL muscle was diminished by ~30% in Sod1KO, but UnAG restored the force deficit by ~80% in the KO mice. We find that upregulation of protein kinase A (PKA) and hyper-phosphorylation of FoxO3a signaling pathways may contribute to the protection. RNA-seq analysis further revealed that UnAG shifted mRNA expression of 366 genes towards younger states that are differentially regulated in old mice. Our data show a direct role of UnAG on sarcopenia independent of changes of food consumption or body weight, implicating UnAG as a potential therapeutic strategy that can enhance quality of life and healthspan of rapidly growing elderly population.

Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men.

To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon-like peptide-1 (GLP-1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration. We examined 10 healthy young men on three separate occasions using a placebo (PBO)-controlled crossover design. A KE versus taste-matched isovolumetric and isocaloric 50% GLU and taste-matched isovolumetric PBO vehicle was orally administered. Our main outcome measures were plasma concentrations of AG, UAG, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 along with appetite sensation scores assessed by visual analogue scale. KE ingestion resulted in an average peak beta-hydroxybutyrate concentration of 5.5 mM. AG and UAG were lowered by approximately 25% following both KE and GLU intake compared with PBO. In the case of AG, the differences were -52.1 (-79.4, -24.8) for KE and -48.4 (-75.4, -21.5) pg/mL for GLU intake (P < .01). Concentrations of AG remained lower with KE but returned to baseline and were comparable with PBO levels after GLU intake. GLP-1, GIP, gastrin and cholecystokinin were not affected by KE ingestion. Our results suggest that the suppressive effects on appetite sensation scores associated with hyperketonaemia are more probable to be mediated through reduced ghrelin concentrations than by increased activity of cholecystokinin, gastrin, GIP or GLP-1.

Unacylated ghrelin, leptin, and appetite display diurnal rhythmicity in lean adults.

Constant routine and forced desynchrony protocols typically remove the effects of behavioral/environmental cues to examine endogenous circadian rhythms, yet this may not reflect rhythms of appetite regulation in the real world. It is therefore important to understand these rhythms within the same subjects under controlled diurnal conditions of light, sleep, and feeding. Ten healthy adults (9 M/1 F, means ±SD: age, 30 ± 10 yr; body mass index, 24.1 ± 2.7 kg·m-2) rested supine in the laboratory for 37 h. All data were collected during the final 24 h of this period (i.e., 0800-0800 h). Participants were fed hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 2200 to 0700 h. Hourly blood samples were collected throughout the 24-h period. Dim light melatonin onset occurred at 2318 ± 46 min. A diurnal rhythm in mean plasma unacylated ghrelin concentration was identified (P = 0.04), with the acrophase occurring shortly after waking (0819), falling to a nadir in the evening with a relative amplitude of 9%. Plasma leptin concentration also exhibited a diurnal rhythm (P < 0.01), with the acrophase occurring shortly after lights-out (0032 h) and the lowest concentrations at midday. The amplitude for this rhythm was 25%. Diurnal rhythms were established in all dimensions of appetite except for sweet preference (P = 0.29), with both hunger (2103 h) and prospective food consumption (1955 h) reaching their peak in the evening before falling to their nadir shortly after waking. Under controlled diurnal conditions, simultaneous measurement of leptin, unacylated ghrelin, and subjective appetite over a 24-h period revealed rhythmicity in appetite regulation in lean, healthy humans.NEW & NOTEWORTHY Simultaneous assessment of subjective appetite, unacylated ghrelin, and leptin was carried out over a continuous 37-h protocol for the first time under conditions of controlled light, sleep, and feeding in healthy, lean adults. Rhythms were observed in unacylated ghrelin, leptin, and components of subjective appetite, such as hunger, prospective consumption, and fullness. Concurrent measurement of rhythms in these variables is important to fully understand the temporal relationships between components of appetite as well as the influence of diurnal factors such as sleep, light, and feeding.

Regulation of adipose tissue lipolysis by ghrelin is impaired with high-fat diet feeding and is not restored with exercise

ABSTRACT Ghrelin is released from the stomach as an anticipatory signal prior to a meal and decreases immediately after. Previous research has shown that both acylated (AG) and unacylated (UnAG) ghrelin blunt adrenoreceptor-stimulated lipolysis in rat white adipose tissue (WAT) ex vivo. We investigated whether acute or chronic consumption of a high fat diet (HFD) impaired the ability of ghrelin to regulate adipose tissue lipolysis, and if this impairment could be restored with exercise. After 5 days (5d) of a HFD, or 6 weeks (6 w) of a HFD (60% kcal from fat) with or without exercise training, inguinal and retroperitoneal WAT was collected from anesthetized rats for adipose tissue organ culture. Samples were treated with 1 μM CL 316,243 (CL; lipolytic control), 1 μM CL+150 ng/ml AG or 1 μM CL+150 ng/ml UnAG. Incubation media and tissue were collected after 2 hours. Colorometric assays were used to determine glycerol and free fatty acid (FFA) concentrations in media. Western blots were used to quantify the protein content of lipolytic enzymes and ghrelin receptors in both depots. CL stimulated lipolysis was evidenced by increases in glycerol (p < 0.0001) and FFA (p < 0.0001) concentrations in media compared to control. AG decreased CL-stimulated glycerol release in inguinal WAT from 5d LFD rats (p = 0.0097). Neither AG nor UnAG blunted lipolysis in adipose tissue from 5d or 6 w HFD-fed rats, and exercise did not restore ghrelin’s anti-lipolytic ability in 6 w HFD-fed rats. Overall, this study demonstrates that HFD consumption impairs ghrelin’s ability to regulate adipose tissue lipolysis.

Thrifty Hormone Ghrelin: The Secret of Aging Muscularly.

Sarcopenia is a debilitating muscle-wasting disease that is the major cause of frailty and disability in aging. Ghrelin (aka acylated ghrelin, AG) is a circulating peptide hormone with an unique octanoylation on Ser3. AG induces growth hormone (GH) secretion, increases food intake, and promotes adiposity and insulin resistance via its receptor, Growth Hormone Secretagogue Receptor (GHS-R). Unlike AG, unacylated ghrelin (UAG) is a peptide generated from the same ghrelin gene with amino acid sequence identical to AG but without the octanoylation modification, so UAG does not activate GHS-R. Intriguingly, both AG and UAG have been shown to promote differentiation and fusion of muscle C2C12 cells, regulate metabolic and mitochondrial signaling pathways in myotubes, and attenuate fasting- or denervation-induced muscle atrophy. Furthermore, it has also been shown that ghrelin gene deficiency increases vulnerability to fasting-induced muscle loss in aging mice, and AG and UAG effectively protects against muscle atrophy of aging mice. Because UAG doesn't bind to GHS-R, it doesn't have the undesired side-effects of elevated GH-release and increased obesity as AG. In summary, UAG has an impressive anti-atrophic effect in muscle protecting against muscle atrophy in aging, it has potential to be a unique and superior therapeutic candidate for muscle-wasting diseases such as sarcopenia.

Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans

SummaryBlood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT−/−) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.

The role of acylated ghrelin and unacylated ghrelin in the blood and hypothalamus and their interaction with nonalcoholic fatty liver disease.

Objective(s):Ghrelin is a brain-gut peptide involved in substance and energy metabolism. To confirm the hypothesis that ghrelin might be involved in non-alcoholic fatty liver disease (NAFLD), a rat NAFLD model was established and the changes of ghrelin were explored.Materials and Methods:The rats were divided into control and NAFLD groups. The rats in the NAFLD group were fed a high-fat–high-cholesterol (HFHC) diet for 8 weeks. Total ghrelin (TG), acylated ghrelin (AG), unacylated ghrelin (UAG), and hypothalamic AG and its receptor GHSR-1a expression were detected using ELISA, RIA, RT-PCR, and Western blot, respectively.Results:Plasma UAG, TG, and the ratio of UAG to AG (UAG/AG) decreased, while protein and mRNA expression of hypothalamic AG and growth hormone secretagogue receptor-1a (GHSR-1a) increased in NAFLD (P<0.01). Plasma UAG and UAG/AG were negatively associated with homeostatic model assessment insulin resistance (HOMA-IR), while AG positively correlated with HOMA-IR (R2=0.6510, P=0.005; R2=0.8520, P=0.000; R2=0.5617, P=0.013, respectively). Plasma UAG, TG and UAG/AG negatively correlated with serum LDL-C or hepatic triglycerides (TGs) (R2=0.7733, P=0.001; R2=0.6930, P=0.003; R2=0.6042, P=0.008; R2=0.7046, P=0.002; R2=0.6722, P=0.004; R2=0.5124, P=0.020, respectively). Hypothalamic AG and GHSR-1a positively correlated with HOMA-IR or hepatic TGs (R2=0.5116, P=0.020; R2=0.5220, P=0.018; R2=0.6074, P=0.008; R2=0.5127, P=0.020, respectively).Conclusion:It might be that decreased circulating UAG/AG, rather than UAG or AG alone, were involved in IR and liver lipid accumulation in NAFLD. Acylated ghrelin might induce IR and promote liver lipid accumulation via a central mechanism involved in the hypothalamus.

Protein Energy Wasting in a Sample of Egyptian Children on Regular Hemodialysis: Relation to Anorexigenic Hormones

BACKGROUND: Increased incidence of pediatric end-stage renal disease (ESRD) with associated serious consequences indicating a major public health problem. Malnutrition and uremic wasting are leading causes of growth impairment and increasing morbidity and mortality of pediatric ESRD patients, predominantly those on regular hemodialysis (HD). Ghrelin and obestatin, which are known appetite regulatory hormones, might have a pivotal role in uremic wasting and growth impairment in hemodialyzed children.&#x0D; AIM: The aim of the present study was to measure serum unacylated ghrelin (UAG) and obestatin and to investigate their roles in the growth impairment of Egyptian hemodialyzed children.&#x0D; SUBJECTS AND METHODS: The study included 50 hemodialyzed and 40 healthy children recruited from the Department of Nephrology, Pediatric Hospital, Ain Shams University. Full clinical examination and measurement of anthropometric indices were done. Routine labs were done as well, with an assessment of serum levels of obestatin, UAG, and insulin by enzyme linked immunosorbent assay. Furthermore, we determined fasting serum glucose and lipid profile with the calculation of homeostasis model assessment for insulin resistance (HOMA-IR).&#x0D; RESULTS: Anthropometric measurements were statistically significantly decreased in the hemodialyzed group than that of the control group (p &lt; 0.05). Weight z-score was the most affected anthropometric parameter (37 patients = 74% with underweight and 13 patients = 26% with normal weight). The hemodialyzed children showed a significant increase of UAG, obestatin, insulin, glucose, HOMA-IR, and TG, while a significant decrease of HDL-cholesterol and albumin (p &lt; 0.01). UAG had a negative correlation with Wt-z score, Ht z-score, fat mass %, albumin, and TG while obestatin was inversely correlated to Wt-z score, BMI z-score, waist circumference, and waist-height ratio (W/H).&#x0D; CONCLUSION: UAG and obestatin hormones were elevated in a group of Egyptian children on regular HD. These hormones were strongly related to the impairment of renal functions, and anthropometric parameters, dyslipidemia, hypoalbuminemia, and insulin resistance in these pediatric hemodialyzed patients.

Both ghrelin deletion and unacylated ghrelin overexpression preserve muscles in aging mice

Both ghrelin deletion and unacylated ghrelin overexpression preserve muscles in aging mice

Both ghrelin deletion and unacylated ghrelin overexpression preserve muscles in aging mice.

Sarcopenia, the decline in muscle mass and functionality during aging, might arise from age-associated endocrine dysfunction. Ghrelin is a hormone circulating in both acylated (AG) and unacylated (UnAG) forms with anti-atrophic activity on skeletal muscle. Here, we show that not only lifelong overexpression of UnAG (Tg) in mice, but also the deletion of ghrelin gene (Ghrl KO) attenuated the age-associated muscle atrophy and functionality decline, as well as systemic inflammation. Yet, the aging of Tg and Ghrl KO mice occurs with different dynamics: while old Tg mice seem to preserve the characteristics of young animals, Ghrl KO mice features deteriorate with aging. However, young Ghrl KO mice show more favorable traits compared to WT animals that result, on the whole, in better performances in aged Ghrl KO animals. Treatment with pharmacological doses of UnAG improved muscle performance in old mice without modifying the feeding behavior, body weight, and adipose tissue mass. The antiatrophic effect on muscle mass did not correlate with modifications of protein catabolism. However, UnAG treatment induced a strong shift towards oxidative metabolism in muscle. Altogether, these data confirmed and expanded some of the previously reported findings and advocate for the design of UnAG analogs to treat sarcopenia.

Three-dimensional growth of breast cancer cells potentiates the anti-tumor effects of unacylated ghrelin and AZP-531

Breast cancer is the most common type of cancer in women and notwithstanding important therapeutic advances, remains the second leading cause of cancer-related death. Despite extensive research relating to the hormone ghrelin, responsible for the stimulation of growth hormone release and appetite, little is known of the effects of its unacylated form, especially in cancer. The present study aimed to characterize effects of unacylated ghrelin on breast cancer cells, define its mechanism of action, and explore the therapeutic potential of unacylated ghrelin or analog AZP-531. We report potent anti-tumor effects of unacylated ghrelin, dependent on cells being cultured in 3D in a biologically-relevant extracellular matrix. The mechanism of unacylated ghrelin-mediated growth inhibition involves activation of Gαi and suppression of MAPK signaling. AZP-531 also suppresses the growth of breast cancer cells in vitro and in xenografts, and may be a novel approach for the safe and effective treatment of breast cancer.