Unacylated Ghrelin Research Articles

The age-associated increment in FIB4, a marker of liver fibrosis, is associated with plasma unacylated ghrelin independently of sex, bmi, insulin resistance and alcohol use frequency

The age-associated increment in FIB4, a marker of liver fibrosis, is associated with plasma unacylated ghrelin independently of sex, bmi, insulin resistance and alcohol use frequency

Hepatoprotective role of unacylated ghrelin in different doses: an experimental study

Hepatoprotective role of unacylated ghrelin in different doses: an experimental study

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults 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. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

Unacylated Ghrelin Protects Against Muscle Wasting, Mitochondrial Dysfunction, and Neuromuscular Junction Disruption in Tumor Bearing Mice

Background: Cancer cachexia is a complex metabolic syndrome that severely impacts mobility, treatment strategies, and life quality of the patients. However, no treatments are available to mitigate the debilitating consequences of cancer cachexia. Ghrelin is a hormone released from the stomach that increases appetite upon acylation by binding to GHSR1a receptors in the brain. Because of its orexigenic effects and increases in body weight, ghrelin GHSR1a receptor analogs were tested as clinical trials to mitigate muscle wasting and loss of strength in cancer patients in several countries. The analogs (i.e., Anamorelin) increased body weight of the non-small lung cancer patients in European countries and Japan, but failed to increase strength, which is the critical component in cancer cachexia. Mainly due to the lack of improvement in strength and patients’ quality of life, Anamorelin was not approved for clinical use in Europe. While the lack of increases in strength is, at least in part, associated with the adipogenic effects of acylated ghrelin, unacylated ghrelin directly improves satellite cell renewal, muscle growth, and mitochondrial function independent of GHSR1a receptor activation and increases in appetite. Unacylated ghrelin is the predominant population in circulation comprising proximately 90-95% of total ghrelin in humans and rodents. Hypothesis: Unacylated ghrelin projects against muscle wasting, loss of strength, and metabolic dysfunction of tumor bearing mice. Methods and Results: Supplementing the cancer cell conditioned medium (CM) with unacylated ghrelin preserved myotube size. Unacylated ghrelin also diminished the cancer cell CM-induced upregulation of MuRF-1, muscle specific ubiquitin ligase. Interestingly, unacylated ghrelin normalized transcriptional upregulation of denervation markers (i.e., sarcolipin, Runx1, GADD45a) in myotubes treated with CM. To further investigate the therapeutic effects of unacylated ghrelin in vivo, we inoculated lung cancer cell line (LL2, ATCC®) in the flank of 4 months old male mice. Two weeks after the injection prior to development of cachexia, mice were provided with unacylated ghrelin containing drinking water or untreated water as control. Tumor bearing (TB) mice treated with unacylated ghrelin showed 30-40% increases in gastrocnemius and quadriceps weights, while soleus muscle mass was unchanged. In addition to the muscle quantity, unacylated ghrelin increased force generating capacity was also improved by unacylated ghrelin. Notably, unacylated ghrelin increased mitochondrial oxygen consumption rate and protected against neuromuscular junction disruption and denervation in TB control mice. Conclusion: Unacylated ghrelin protects against cancer cachexia by targeting multiple risk factors in skeletal muscle wasting, including protein balance, metabolic alterations, and neuromuscular junction disruption. Our findings show protective effects of unacylated ghrelin against cachexia and neuromuscular impairment in tumor bearing mice, indicating its therapeutic potential in cancer patients. NIA R00 064143 to Ahn B. Pilot funds from the Center for Redox Biology in Medicine, and Cancer Genetics and Metabolism program at the Wake Forest Baptist Comprehensive Cancer Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway.

Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.

Unacylated ghrelin attenuates acute liver injury and hyperlipidemia via its anti-inflammatory and anti-oxidative activities.

Liver injury and hyperlipidemia are major issues that have drawn more and more attention in recent years. The present study aimed to investigate the effects of unacylated ghrelin (UAG) on acute liver injury and hyperlipidemia in mice. UAG was injected intraperitoneally once a day for three days. Three hours after the last administration, acute liver injury was induced by intraperitoneal injection of carbon tetrachloride (CCl4), and acute hyperlipidemia was induced by intraperitoneal injection of poloxamer 407, respectively. Twenty-four hours later, samples were collected for serum biochemistry analysis, histopathological examination, and Western blotting. In acute liver injury mice, UAG significantly decreased liver index, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), reduced malondialdehyde (MDA) concentration and increased superoxide dismutase(SOD) in liver tissue. NF-kappa B (NF-κB) protein expression in the liver was down-regulated. In acute hyperlipidemia mice, UAG significantly decreased serum total cholesterol (TC), triglyceride (TG), ALT, and AST, as well as hepatic TG levels. Meanwhile, hepatic MDA decreased and SOD increased significantly. Moreover, UAG improved the pathological damage in the liver induced by CCl4 and poloxamer 407, respectively. Intraperitoneal injection of UAG exhibited hepatoprotective and lipid-lowering effects on acute liver injury and hyperlipidemia, which is attributed to its anti-inflammatory and anti-oxidant activities.

Longitudinal Changes in Acylated versus Unacylated Ghrelin Levels May Be Involved in the Underlying Mechanisms of the Switch in Nutritional Phases in Prader-Willi Syndrome

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite-regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls. Methods: A longitudinal study was conducted in 134 children with PWS and 157 healthy controls, from the Netherlands, France, and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored. Results: The AG/UAG ratio was lower in the first years of life in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p = 0.114), while the UAG levels decreased from 290 pg/mL in phase 1a to 137 pg/mL in phase 2b (p < 0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p = 0.012). Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia.

Stimulation of fat oxidation in rat muscle by unacylated ghrelin persists for 2-3 hours, but is independent of fatty acid transporter translocation.

While a definitive mechanism-of-action remains to be identified, recent findings indicate that ghrelin, particularly the unacylated form (UnAG), stimulates skeletal muscle fatty acid oxidation. The biological importance of UnAG-mediated increases in fat oxidation remains unclear, as UnAG peaks in the circulation before mealtimes, and decreases rapidly during the postprandial situation before increases in postabsorptive circulating lipids. Therefore, we aimed to determine if the UnAG-mediated stimulation of fat oxidation would persist long enough to affect the oxidation of meal-derived fatty acids, and if UnAG stimulated the translocation of fatty acid transporters to the sarcolemma as a mechanism-of-action. In isolated soleus muscle strips from male rats, short-term pre-treatment with UnAG elicited a persisting stimulus on fatty acid oxidation 2 h after the removal of UnAG. UnAG also caused an immediate phosphorylation of AMPK, but not an increase in plasma membrane FAT/CD36 or FABPpm. There was also no increase in AMPK signaling or increased FAT/CD36 or FABPpm content at the plasma membrane at 2 h which might explain the sustained increase in fatty acid oxidation. These findings confirm UnAG as a stimulator of fatty acid oxidation and provide evidence that UnAG may influence the handling of postprandial lipids. The underlying mechanisms are not known.

Acylated- and unacylated ghrelin during an oral glucose tolerance test in humans at risk for type 2 diabetes mellitus

Background/ObjectivesThe orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity.Subjects/MethodsIn this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²–76.25 kg/m²).ResultsFasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90–120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m².ConclusionOur data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.

Sarcopenic obesity in free-living older adults detected by the ESPEN-EASO consensus diagnostic algorithm: Validation in an Italian cohort and predictive value of insulin resistance and altered plasma ghrelin profile

Aging and obesity are synergistic sarcopenia risk factors (RF). Their association in sarcopenic obesity (SO) enhances morbidity and mortality, but consensus on SO diagnostic criteria is limited. ESPEN and EASO issued a consensus algorithm for SO screening (obesity and clinical SO suspicion) and diagnosis [low muscle strength by hand-grip (HGS) and low muscle mass by BIA], and we investigated its implementation in older adults (>65-years), as well as SO-associated metabolic RF [insulin resistance (IR: HOMA) and plasma acylated (AG) and unacylated (UnAG) ghrelin, with predictive value also assessed from 5-year-prior observations]. Older adults with obesity from the Italian MoMa study on metabolic syndrome in primary care (n = 76) were studied. 7 of 61 individuals with positive screening had SO (SO+; 9 % of cohort). No individuals with negative screening had SO. SO+ had higher IR, AG and plasma AG/UnAG ratio (p < 0.05 vs negative screening and SO-), and both IR and ghrelin profile predicted 5-year SO risk independent of age, sex and BMI. The current results provide the first ESPEN-EASO algorithm-based investigation of SO in free-living older adults, with 9 % prevalence in those with obesity and 100 % algorithm sensitivity, and they support IR and plasma ghrelin profile as SO risk factors in this setting.

Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies

BackgroundObesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the ‘inactive’ unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake. AimsTo report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity. MethodsThe SRD study investigated single doses of BI 1356225 (0.1–20.0 mg) in healthy male subjects with a BMI of 18.5–29.9 kg/m2 (SRD cohort) and assessed doses of 2.5 mg BI 1356225 under fed and fasted conditions (bioavailability [BA] cohort). The MRD study investigated multiple doses of BI 1356225 (0.2, 1.0, 2.5 or 10.0 mg) or 5.0 mg BI 1356225 with a single dose of midazolam and celecoxib (drug–drug interaction part) over 28 days in adults with a BMI of 27.0–39.9 kg/m2. ResultsSixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration–time curve [AUC] and maximum plasma concentration [Cmax]) of BI 1356225 increased across dose groups, although this was less than dose-proportional across the entire dose range. In the BA cohort of the SRD study, AUC0–∞ was slightly increased and Cmax slightly decreased in fed versus fasted conditions, with fed/fasted ratios (90 % CI) of 101.10 % (92.42, 110.60) and 91.67 % (78.50, 107.05), respectively. In both studies, AG concentrations and the AG/UAG ratio were dose-dependently decreased after BI 1356225 treatment from baseline versus placebo. In the MRD study, UAG concentrations were increased from baseline, but not dose-dependently. No differences were observed in bodyweight, appetite, food cravings, ad libitum food uptake or obesity-related biomarkers after 28 days of treatment with BI 1356225. ConclusionsTreatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.

Ghrelin regulates the proliferation and apoptosis of high glucose‐induced islet cells through the PI3K–Akt signaling pathway

Ghrelin may have therapeutic value in mitigating insulin resistance and type 2 diabetes, based on which we further explore the action mechanism of ghrelin on islet cells in this research. In the course of experiments, MIN6 cells were induced by glucose and then treated with acylated or unacylated ghrelin. The effects of ghrelin on the viability, proliferation, apoptosis, and insulin release of high glucose-induced islet cells were detected by CellCounting Kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, and enzyme-linked immunosorbent assays, respectively. Meanwhile, cells were treated with LY294002 to explore whether and how the inhibited phosphoinositide 3-kinase-protein kinase B(PI3K-AKT) signaling pathway participated in the internal mechanism of ghrelin-regulating islet cells. Western blotting was performed to quantify the expression levels of Bcl-2, Bax, Cleaved caspase-3, PI3K, and AKT. As a result, ghrelin alleviated high glucose-induced suppression of viability and proliferation and promotion on apoptosis of MIN6 cells. Ghrelin also attenuated the inhibitory effects of high glucose on expression levels of PI3K-Akt signaling axis-related proteins and insulin release in MIN6 cells. Besides, ghrelin weakened the impacts of high glucose on boosting MIN6 cell apoptosis and hindering proliferation through thePI3K-Akt signaling axis. Collectively, ghrelin regulates the proliferation and apoptosis of high glucose-induced islet cells through the PI3K-Akt signaling pathway.

Clinical Trials in Prader-Willi Syndrome: A Review.

Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.

Acylated Ghrelin Receptor Agonist HM01 Decreases Lean Body and Muscle Mass, but Unacylated Ghrelin Protects against Redox-Dependent Sarcopenia.

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 upon acylation, which activates its receptor GHSR1a. Recent studies have demonstrated that acyl and unacylated ghrelin are protective against acute pathological conditions of skeletal muscle. We hypothesized that both acyl ghrelin receptor agonist (HM01) and unacylated ghrelin ameliorate muscle atrophy and contractile dysfunction in oxidative stress-induced sarcopenia. HM01, unacylated ghrelin, or saline was delivered via osmotic pump. HM01 increased food consumption transiently, while the body weight remained elevated. It also decreased lean body mass and muscle mass of wildtype and Sod1KO. In contrast, unacylated ghrelin ameliorated loss of muscle mass by 15-30% in Sod1KO mice without changes in food consumption or body weights. Contractile force was decreased by ~30% in Sod1KO mice, but unacylated ghrelin prevented the force deficit by ~80%. We identified downregulation of transcription factor FoxO3a and its downstream E3 ligase MuRF1 by unacylated ghrelin. Our data show a direct role of unacylated ghrelin in redox-dependent sarcopenia independent of changes of food consumption or body weight.

Development of Esterase-Resistant and Highly Active Ghrelin Analogs via Thiol-Ene Click Chemistry.

The orexigenic peptide ghrelin exerts important functions in energy metabolism and has therapeutic potential to treat certain diseases. Native ghrelin carries an essential O-fatty acyl moiety; however, this post-translational modification is susceptible to hydrolysis by certain esterases in circulation, representing a major route of its in vivo inactivation. In the present study, we developed a novel approach to prepare various esterase-resistant ghrelin analogs via photoinduced thiol-ene click chemistry. A recombinant unacylated human ghrelin mutant was reacted with commercially available terminal alkenes; thus, various alkyl moieties were introduced to the side chain of its unique Cys3 residue via a thioether bond. Among 11 S-alkylated ghrelin analogs, analog 11, generated by reacting with 2-methyl-1-octene, not only acquired much higher stability in serum but also retained full activity compared with native human ghrelin. Thus, the present study provided an efficient approach to prepare highly stable and highly active ghrelin analogs with therapeutic potential.

Ghrelin, growth hormone and insulin-like growth Factor-I levels in people with protein C deficiency

The primary objective of this study was to examine if people with protein C deficiency, which is a natural anticoagulant and also an endogenous acyl ghrelin peptidase, have elevated circulating levels of acyl ghrelin. The clinical trial was conducted in a university hospital setting. People with protein C deficiency were identified and invited to participate by a specialized coagulation outpatient clinic. People with protein C deficiency were examined and compared to age, sex, and body mass index matched healthy controls with regards to acyl ghrelin, unacylated ghrelin, growth hormone (GH) and insulin-like growth-factor I (IGF-I) in a cross-sectional case-control study. Systemic levels of acyl ghrelin, desacyl ghrelin, acyl-to-desacyl ghrelin ratio, GH and IGF-I were similar in people with protein C deficiency and healthy controls. Despite a significant reduction of protein C in people with protein C deficiency, there was no difference in acyl ghrelin or the secondary end points unacylated ghrelin, GH, or IGF-I in people with protein C deficiency.

Multiple roles of ghrelin in breast cancer.

Breast cancer is one of the most threatening malignant tumors in women worldwide; hence, investigators are continually performing novel research in this field. However, an accurate prediction of its prognosis and postoperative recovery remains difficult. The severity of breast cancer is patient-specific and affected by several health factors; thus, unknown mechanisms may affect its progression. This article analyzes existing literature on breast cancer, ranging from the discovery of ghrelin to its present use, and aims to provide a reference for future research into breast cancer mechanisms and treatment-plan improvement. Various parts of ghrelin have been associated with breast cancer by direct or indirect evidence. The ghrelin system may encompass the direction of expanding breast cancer treatment methods and prognostic indicators. Therefore, we compiled almost all studies on the relationship between the ghrelin system and breast cancer, including unacylated ghrelin, its GHRL gene, ghrelin O-acyltransferase, the receptor growth hormone secretagogue receptor, and several splice variants of ghrelin to lay the foundation for future research.

Exogenous administration of unacylated ghrelin attenuates hepatic steatosis in high-fat diet-fed rats by modulating glucose homeostasis, lipogenesis, oxidative stress, and endoplasmic reticulum stress

Low levels of unacylated ghrelin (UAG) and a higher ratio of acylated ghrelin (AG)/UAG in obesity are associated with non-alcoholic fatty liver disease (NAFLD). This study tested the potential protective effect of increased circulatory levels of UAG by exogenous UAG administration on hepatic steatosis in high-fat diet (HFD)-fed rats and investigated some possible mechanisms. Rats were divided (n = 6/group) as low fat diet (LFD), LFD + UAG (200 mg/kg), HFD, HFD + UAG (50, 100, or 200 mg/kg). Treatments were given for 8 weeks. Increasing the dose of UAG increased circulatory levels of UAG and normalized the ratio of AG/UAG at the dose of 200 mg/kg. With no change in insulin levels, and in a dose-dependent manner, treatment with UAG to HFD rats attenuated the gain in food intake, body weights, and liver weights, lowered fasting glucose levels, prevented hepatic cytoplasmic vacuolization, and reduced serum and hepatic levels of cholesterol, triglycerides, and free fatty acids. They also progressively reduced levels of reactive oxygen species, lipid peroxides, tumor necrosis factor-α, and interleukin-6, as well as mRNA levels of Bax and caspase-3 but increased levels of glutathione and superoxide dismutase and mRNA levels of Bcl2. In concomitant, UAG, in a dose-response manner, significantly reduced hepatic mRNA levels of SREBP1, SREBP2, ATF-6, IRE-1, and eIF-2α but increased those of PPARα. In conclusion, reducing the circulatory ratio of AG/UAG ratio by exogenous administration of UAG attenuates HFD-induced hepatic steatosis by suppressing lipogenesis, stimulating FAs oxidation, preventing oxidative stress, inflammation, ER stress, and apoptosis.

Ghrelin Levels in Children With Intestinal Failure Receiving Long-Term Parenteral Nutrition.

BackgroundChildren with intestinal failure (IF) require parenteral nutrition (PN). Transition to oral and enteral nutrition (EN) can be difficult also due to abnormal gastrointestinal motility. The gut hormone ghrelin is increased in states of negative energy balance, functioning to preserve euglycemia, and also has appetite stimulating and prokinetic properties. We aimed to evaluate and compare ghrelin levels in children with IF, and to assess the relationship with PN-dependency.MethodsIn this exploratory prospective multicenter study, plasma acylated (AG) and unacylated (UAG) ghrelin levels were measured in children with short bowel syndrome (SBS) and with functional IF (pseudo-obstruction or any enteropathy) and compared with healthy control subjects. Spearman’s rho (rs) was used to assess correlations of AG and UAG with PN-dependency (%PN) and parenteral glucose intake.ResultsSixty-four samples from 36 IF-patients were analyzed. Median baseline AG and UAG levels were respectively 279.2 and 101.0 pg/mL in children with SBS (n = 16), 126.4 and 84.5 pg/mL in children with functional IF (n = 20) and 82.4 and 157.3 pg/mL in healthy children (n = 39). AG levels were higher in children with SBS and functional IF than in healthy children (p = 0.002 and p = 0.023, respectively). In SBS, AG positively correlated with %PN (rs = 0.5, p = 0.005) and parenteral glucose intake (rs = 0.6, p = 0.003). These correlations were not observed in functional IF.ConclusionChildren with IF had raised AG levels which could be related to starvation of the gut. The positive correlation between AG and glucose infusion rate in SBS suggests an altered glucoregulatory function.

Ghrelin and Cancer: Examining the Roles of the Ghrelin Axis in Tumor Growth and Progression.

Ghrelin, a hormone produced and secreted from the stomach, is prim arily known as an appetite stimulant. Recently, it has emerged as a potential regulator/biomarker of cancer progression. Inconsistent results on this subject make this body of literature difficult to interpret. Here, we attempt to identify commonalities in the relationships between ghrelin and various cancers, and summarize important considerations for future research. The main players in the ghrelin family axis are unacylated ghrelin (UAG), acylated ghrelin (AG), the enzyme ghrelin O-acyltransferase (GOAT), and the growth hormone secretagogue receptor (GHSR). GOAT is responsible for the acylation of ghrelin, after which ghrelin can bind to the functional ghrelin receptor GHSR-1a to initiate the activation cascade. Splice variants of ghrelin also exist, with the most prominent being In1-ghrelin. In this review, we focus primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts. Further understanding of the role of the ghrelin axis in tumor cell proliferation could lead to the development of novel therapeutic approaches for various cancers.