Colonic Medium-Chain Fatty Acids Act as a Source of Energy and for Colon Maintenance but Are Not Utilized to Acylate Ghrelin.

The capacity of microbiota to produce medium-chain fatty acids (MCFA) and related consequences for the gastrointestinal (GI) tract have never been reported before. We verified the impact of nutrition-related factors on fatty acid (FAs) production and found that caloric restriction decreased levels of most of MCFAs in the mouse cecum, whereas overnight fasting reduced the levels of acetate and butyrate but increased propionate and laurate. A diet high in soluble fibre boosted the production of short-chain fatty acids (SCFA) and caproate whereas a high-cellulose diet did not have an effect or decreased the levels of some of the FAs. Rectal infusion of caprylate resulted in its rapid metabolism for energy production. Repeated 10-day MCFA infusion impacted epididymal white adipose tissue (eWAT) weight and lipid accumulation. Repeated infusion of caprylate rectally tended to increase the concentration of active ghrelin in mice plasma; however, this increase was not statistically significant. In Caco-2 cells, caprylate increased the expression of Fabp2, Pdk4, Tlr3, and Gpr40 genes as well as counteracted TNFα-triggered downregulation of Pparγ, Occludin, and Zonulin mRNA expression. In conclusion, we show that colonic MCFAs can be rapidly utilized as a source of energy or stored as a lipid supply. Further, locally produced caprylate may impact metabolism and inflammatory parameters in the colon.

High Coexpression of the Ghrelin and LEAP2 Receptor GHSR With Pancreatic Polypeptide in Mouse and Human Islets.

Islets represent an important site of direct action of the hormone ghrelin, with expression of the ghrelin receptor (growth hormone secretagogue receptor; GHSR) having been localized variably to alpha cells, beta cells, and/or somatostatin (SST)-secreting delta cells. To our knowledge, GHSR expression by pancreatic polypeptide (PP)-expressing gamma cells has not been specifically investigated. Here, histochemical analyses of Ghsr-IRES-Cre × Cre-dependent ROSA26-yellow fluorescent protein (YFP) reporter mice showed 85% of GHSR-expressing islet cells coexpress PP, 50% coexpress SST, and 47% coexpress PP + SST. Analysis of single-cell transcriptomic data from mouse pancreas revealed 95% of Ghsr-expressing cells coexpress Ppy, 100% coexpress Sst, and 95% coexpress Ppy + Sst. This expression was restricted to gamma-cell and delta-cell clusters. Analysis of several single-cell human pancreatic transcriptome data sets revealed 59% of GHSR-expressing cells coexpress PPY, 95% coexpress SST, and 57% coexpress PPY + SST. This expression was prominent in delta-cell and beta-cell clusters, also occurring in other clusters including gamma cells and alpha cells. GHSR expression levels were upregulated by type 2 diabetes mellitus in beta cells. In mice, plasma PP positively correlated with fat mass and with plasma levels of the endogenous GHSR antagonist/inverse agonist LEAP2. Plasma PP also elevated on LEAP2 and synthetic GHSR antagonist administration. These data suggest that in addition to delta cells, beta cells, and alpha cells, PP-expressing pancreatic cells likely represent important direct targets for LEAP2 and/or ghrelin both in mice and humans.

Defective dystrophic thymus determines degenerative changes in skeletal muscle.

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-ß and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.

Salivary concentrations of cytokines and other analytes in healthy children.

BACKGROUND: Blood has been the usual biological fluid for measuring analytes, but there is mounting evidence that saliva may be also useful for detecting cytokines in a noninvasive way. Thus, in this study we aimed to determine concentration of cytokines and other analytes in saliva from a population of healthy children. METHODS: We collected un-stimulated whole saliva samples from clinically healthy children, and concentration of 17 cytokines and 12 other analytes were measured in supernatants. All values were adjusted by albumin content and were log-transformed before multivariate statistical analysis. RESULTS: We included 114 children (53.5% females) between 6.0 and 11.9 years old. The highest concentrations (medians, pg/µg albumin) were seen for visfatin (183.70) and adiponectin (162.26) and the lowest for IL-13 and IL-2 (~0.003). Albumin concentration was associated with age (rS = 0.39, p < 0.001). In the multivariate analysis, five analytes (C peptide, ghrelin, GLP-1, glucagon, leptin) inversely correlated with age and positively with height-for-age. Age was also positively associated with PAI-1, while height-for-age was also positively associated with insulin and visfatin. Finally, BMI-for-age had a positive correlation with GM-CSF and insulin. CONCLUSIONS: Herein, we provided concentration values for 29 analytes in saliva from healthy children that may be useful as preliminary reference framework in the clinical research setting.

ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice.

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient (Adar1+/-) mice were fed normal chow or a high-fat diet (HFD) for 12 wk. Adar1+/- mice fed with HFD exhibited a lean phenotype with reduced fat mass compared with WT controls, although no difference was found under chow diet conditions. Blood biochemical analysis and insulin tolerance test showed that Adar1+/- improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in Adar1+/- mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that Adar1+/- protected mice from HFD-induced obesity through decreased food intake. Furthermore, Adar1+/- restored the increased ghrelin expression in the stomach and the decreased serum peptide YY levels under HFD conditions. These data indicate that ADAR1 may contribute to diet-induced obesity, at least partially, through modulating the ghrelin and peptide YY expression and secretion.NEW & NOTEWORTHY This study identifies adenosine deaminase acting on RNA 1 as a novel factor promoting high-fat diet-induced obesity, at least partially, through modulating appetite-related genes ghrelin and PYY.

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.

Nutritional programming improves dietary plant protein utilization in zebrafish Danio rerio.

Nutritional Programming (NP) has been shown to counteract the negative effects of dietary plant protein (PP) by introducing PP at an early age towards enhancement of PP utilization during later life stages. This study explored the effect of NP and its induction time on growth, expression of appetite-stimulating hormones, and any morphological changes in the gut possibly responsible for improved dietary PP utilization. At 3 days post-hatch (dph) zebrafish were distributed into 12 (3 L) tanks, 100 larvae per tank. This study included four groups: 1) The control (NP-FM) group received fishmeal (FM)-based diet from 13-36 dph and was challenged with PP-based diet during 36-66 dph; 2) The NP-PP group received NP with dietary PP in larval stage via live food enrichment during 3-13 dph followed by FM diet during 13-36 dph and PP diet during 36-66 dph; 3) The T-NP group received NP between 13-23 dph through PP diet followed by FM diet during 23-36 dph and PP diet during 36-66 dph; and 4) The PP group received PP diet from 13-66 dph. During the PP challenge the T-NP group achieved the highest weight gain compared to control and PP. Ghrelin expression in the brain was higher in T-NP compared to NP-FM and NP-PP, while in the gut it was reduced in both NP-PP and T-NP groups. Cholecystokinin expression showed an opposite trend to ghrelin. The brain neuropeptide Y expression was lower in NP-PP compared to PP but not different with NP-FM and T-NP groups. The highest villus length to width ratio in the middle intestine was found in T-NP compared to all other groups. The study suggests that NP induced during juvenile stages improves zebrafish growth and affects digestive hormone regulation and morphology of the intestinal lining-possible mechanisms behind the improved PP utilization in pre-adult zebrafish stages.

Pancreas is a preeminent source of ghrelin after sleeve gastrectomy in Wistar rats.

Many surgical techniques are employed in the treatment of severe obesity. A main consequence of these techniques is the improvement of type 2 Diabetes mellitus. Ghrelin is a gut hormone released in the gastric fundus and corpus, which has been related to diabetic improvement as mentioned in these papers. Sleeve gastrectomy and Roux-en Y Gastric Bypass are surgical techniques broadly employed in humans; both severely reduce the gastric surface. Paradoxically, the serum level of ghrelin in patients is preserved. We hypothesized about the role of embryonic pancreatic epsilon cells, which have the capacity to release ghrelin. We studied the changes in the epsilon cells and differentiation markers with immunostaining and ghrelin serum level and after surgery. We employed euglycemic male Wistar rats: two surgical groups (Sleeve gastrectomy and Roux-en Y Gastric Bypass) and two control groups. We reported a significant increase of ghrelin epsilon-cells in the pancreas and basal serum after Sleeve gastrectomy versus the control groups. The epsilon cellular increment was related to neogenesis, as the neurogenin-3 marker revealed. The Roux-en Y Gastric Bypass showed neither epsilon cell increase nor basal serum changes in ghrelin release. As a conclusion, we reported that the severe suppression of the fundus gastric produced the recovery of ghrelin released by the epsilon cells, which was indicative of an ontogenic embryonic pancreatic function.

Expression of ghrelin and leptin in the chemosensory system of adult zebrafish.

Numerous data show that the chemosensory system seems to be modulated by changes in the circulating levels of different molecules such as ghrelin, orexin, leptin, NPY, CCK. The chemosensory system of the zebrafish is represented by the taste buds (skin, oral and oropharyngeal), the olfactory rosette and the solitary chemosensorial cells (SCCs). The purpose of our study was to analyze the distribution of two peripheral hormones such as ghrelin and leptin in the chemosensory organs of the zebrafish. Our results demonstrated the presence of immunoreaction for all antibodies used in the zebrafish chemosensory organs even if with different distribution. In particular, IR was observed for ghrelin in the olfactory rosette while IR for leptin was found in the olfactory rosette, in the skin and oropharyngeal taste buds and in the gills. Both these hormones were detected in the intestine, used as a control.

Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production.

BACKGROUND: Pancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear. METHODS: We established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1flox/flox mice were bred with Ghrl-cre mice to generate Ghrl-TSC1-/- (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice. FINDINGS: Activation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis. INTERPRETATION: Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin.

Molecular cloning and expression of ghrelin in the hypothalamus-pituitary-gastrointestinal tract axis of the Yak (Bos grunniens) in the Qinghai-Tibetan Plateau.

Ghrelin is a very important brain-gut peptide that modulates appetite and energy metabolism in mammals. The yak is the only large mammal that can adapt to the cold temperatures and hypoxia conditions present in the Qinghai-Tibet Plateau. However, there are no reports on ghrelin molecular characterization and expression in the hypothalamus-pituitary-digestive tract axis of the yak to date. In this study, the coding region sequence of the yak ghrelin, containing a complete ORF (351) encoding for 117 amino acids, was cloned. Immunohistochemistry analysis of the yak samples showed that ghrelin-immunoreactive cells were expressed at the arcuate nucleus (ARC), the ventromedial nucleus (VMN), the dorsomedial nucleus (DMN) of the hypothalamus and also at the anterior pituitary. Ghrelin-positive cells were also present in approximately two thirds of the submucosa of the abomasum fundic gland and mucous layer of the duodenum intestinal gland. Ghrelin's mRNA highest expression occurred in the abomasum sample, followed by the duodenum, hypothalamus and lowest at the pituitary gland. The level of ghrelin mRNA measured in yak was higher than in cattle for all the tissues that were compared. The ghrelin protein and mRNA expression profiles were similar. These data imply that the high expression of ghrelin in the hypothalamus-pituitary-digestive tract axis of yak could aid adaptation to the extreme environment better than cattle, by improving appetite and fat accumulation, regulating body temperature and reducing energy consumption via regulating energy metabolism.

Hypothalamic peroxisome proliferator-activated receptor gamma regulates ghrelin production and food intake.

Peroxisome proliferator-activated receptor-γ (PPARγ) regulates fatty acid storage, glucose metabolism, and food intake. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. However, the effects of PPARγ on ghrelin production are still unclear. In the present study, the effects of PPARγ on ghrelin production were examined in lean- or high-fat diet-induced obese (DIO) C57BL/6J mice and mHypoE-42 cells, a hypothalamic cell line. 3rd intracerebroventricular injection of adenoviral-directed overexpression of PPARγ (Ad-PPARγ) reduced hypothalamic and plasma ghrelin, food intake in both lean C57BL/6J mice and diet-induced obese mice. These changes were associated with a significant increase in mechanistic target of rapamycin complex 1 (mTORC1) activity. Overexpression of PPARγ enhanced mTORC1 signaling and suppressed ghrelin production in cultured mHypoE-42 cells. Our results suggest that hypothalamic PPARγ plays a vital role in ghrelin production and food intake in mice.

Biochemical properties and biological actions of obestatin and its relevence in type 2 diabetes.

Obestatin was initially discovered in rat stomach extract, and although it is principally produced in the gastric mucosa, it can be found throughout the gastrointestinal tract. This 23-amino acid C-terminally amidated peptide is derived from preproghrelin and has been ascribed a wide range of metabolic effects relevant to type 2 diabetes. Obestatin reportedly inhibits gastrointestinal motility, reduces food intake and lowers body weight and improves lipid metabolism. Furthermore, it appears to exert actions on the pancreatic ß-cell, most notably increasing ß-cell mass and upregulating genes associated with insulin production and ß-cell regeneration, with relevance to type 2 diabetes. It is becoming evident that obestatin also exerts pleiotropic effects on the cardiovascular system, possibly modulating blood pressure, endothelial function and triggering cardioprotective mechanisms, which may be important in determining cardiovascular outcomes in type 2 diabetes. Furthermore, it seems that like other gut peptides obestatin has neuroprotective properties. This review examines the biochemical properties of the obestatin peptide (its structure, sequence, stability and distribution) and the candidate receptors through which it may act. It provides a balanced examination of the reported pancreatic and extrapancreatic actions of obestatin and evaluates its potential relevance with respect to diabetes therapy, together with discussion of direct evidence linking alterations in obestatin signalling with obesity/diabetes and other diseases.

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model.

Purpose: Ghrelin, a natural ligand for the growth hormone secretagogue receptor type 1a (GHSR-1a), may protect retinal neurons against glaucomatous injury. We therefore characterized the underlying mechanism of the ghrelin/GHSR-1a-mediated neuroprotection with a rat chronic intraocular hypertension (COH) model. Methods: The rat COH model was produced by blocking episcleral veins. A combination of immunohistochemistry, Western blot, TUNEL assay, and retrograde labeling of retinal ganglion cells (RGCs) was used. Results: Elevation of intraocular pressure induced a significant increase in ghrelin and GHSR-1a expression in retinal cells, including RGCs and Müller cells. Western blot confirmed that the protein levels of ghrelin exhibited a transient upregulation at week 2 after surgery (G2w), while the GHSR-1a protein levels were maintained at high levels from G2w to G4w. In COH retinas, the ratio of LC3-II/LC-I and beclin1, two autophagy-related proteins, were increased from G1w to G4w, and the cleavage product of caspase3, an apoptotic executioner, was detected from G2w to G4w. Intraperitoneal injection of ghrelin significantly increased the number of surviving RGCs; inhibited the changes of LC3-II/LC-I, beclin1, and the cleavage products of caspase3; and reduced the number of TUNEL-positive cells in COH retinas. Ghrelin treatment also reversed the decreased levels of p-Akt and p-mTOR, upregulated GHSR-1a protein levels, and attenuated glial fibrillary acidic protein levels in COH retinas. Conclusions: All these results suggest that ghrelin may provide neuroprotective effect in COH retinas through activating ghrelin/GHSR-1a system, which was mediated by inhibiting retinal autophagy, ganglion cell apoptosis, and Müller cell gliosis.

Endogenous peptide profile for elucidating biosynthetic processing of the ghrelin precursor.

Ghrelin is an orexigenic peptide primarily produced by gastric endocrine cells. The biosynthetic cleavage site of ghrelin has been well documented, but how its downstream region undergoes proteolytic processing remains poorly explored. Here, we provide the first snapshot of endogenous peptides from the ghrelin precursor by profiling the secretopeptidome of cultured mouse ghrelin-producing cells during exocytosis. Mapping of MS/MS sequenced peptides to the precursor highlighted three atypical monobasic processing sites, including the established C-terminus of ghrelin and the N-terminal cleavage site for obestatin, a putative 23-amino-acid C-terminally amidated peptide. However, we found that mouse obestatin does not occur in the form originally reported, but that a different amidation site is used to generate a shorter peptide. These data can be extended to study and characterize the precursor-derived peptides located downstream of ghrelin in different biological contexts.

Is Ghrelin Synthesized in the Central Nervous System?

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

IL-1ß directly suppress ghrelin mRNA expression in ghrelin-producing cells.

In animal models, ghrelin production is suppressed by LPS administration. To elucidate the detailed molecular mechanisms involved in the phenomenon, we investigated the effects of LPS and LPS-inducible cytokines, including TNF-α, IL-1ß, and IL-6, on the expression of ghrelin in the ghrelin-producing cell line MGN3-1. These cells expressed IL-1R, and IL-1ß significantly suppressed ghrelin mRNA levels. The suppressive effects of IL-1ß were attenuated by knockdown of IKKß, suggesting the involvement of the NF-κB pathway. These results suggested that IL-1ß is a major regulator of ghrelin expression during inflammatory processes.

Influence of preterm delivery on ghrelin and obestatin concentrations in maternal plasm, milk and their expression in mammary epithelial cells.

Ghrelin and obestatin are gastrointestinal peptides with a potential role in the programming of metabolism in newborns. The present study aimed to investigate the influence of preterm delivery on ghrelin and obestatin concentrations in the maternal blood plasma and breast milk as well as their gene expressions in the mammary epithelial cells (MECs). On the 3rd day after delivery, milk and plasma samples were collected from mothers that carried to term or gave birth prematurely (< 36 weeks of gestation) and analyzed for ghrelin and obestatin concentrations. MECs isolated from the milk were analyzed for the relative expression of GHRL splice variants. In both groups ghrelin concentrations were significantly lower in milk than in blood plasma. In the preterm group obestatin concentrations were significantly higher in milk than in blood plasma but significantly lower in comparison to that of the control mothers. The expression of GHRL mRNAs was higher (P < 0.05) in MECs isolated from the preterm group as compared to those isolated from control mothers. The concentration of obestatin (but not ghrelin) in the breast milk is dependent on the term of pregnancy. Moreover, the lactating mammary gland is one of the sources of ghrelin and obestatin.

Exendin-4 decreases ghrelin levels through mTOR signaling.

Exendin-4 (EX-4), a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, regulates feeding behavior through its ability to inhibit gastric emptying. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. Here, we report that EX-4 suppresses ghrelin production through the mTORC1-dependent mechanism. Central administration of EX-4 reduces gastric, hypothalamic and plasma ghrelin in both C57BL/6J mice and diet induced obese mice. These changes were associated with a significant increase in mTORC1 activity. Both GLP-1 and EX-4 suppressed the expression and secretion of ghrelin in cultured mHypoE-42 cells, a hypothalamic cell line. These effects were associated with significant changes in mTOR signaling. Inhibition of mTORC1 activity by mTOR siRNA or rapamycin abolished the suppression of ghrelin production induced by GLP-1 and EX-4 in mHypoE-42 cells. Our results identify mTORC1 as a critical signaling pathway for the downregulation of ghrelin induced by activation of GLP-1R.

Ghrelin and the Cardiovascular System.

Ghrelin is a small peptide released primarily from the stomach. It is a potent stimulator of growth hormone secretion from the pituitary gland and is well known for its regulation of metabolism and appetite. There is also a strong relationship between ghrelin and the cardiovascular system. Ghrelin receptors are present throughout the heart and vasculature and have been linked with molecular pathways, including, but not limited to, the regulation of intracellular calcium concentration, inhibition of proapoptotic cascades, and protection against oxidative damage. Ghrelin shows robust cardioprotective effects including enhancing endothelial and vascular function, preventing atherosclerosis, inhibiting sympathetic drive, and decreasing blood pressure. After myocardial infarction, exogenous administration of ghrelin preserves cardiac function, reduces the incidence of fatal arrhythmias, and attenuates apoptosis and ventricular remodeling, leading to improvements in heart failure. It ameliorates cachexia in end-stage congestive heart failure patients and has shown clinical benefit in pulmonary hypertension. Nonetheless, since ghrelin's discovery is relatively recent, there remains a substantial amount of research needed to fully understand its clinical significance in cardiovascular disease.