Structure and Physiological Functions of Ghrelin and Physiological Functions of Ghrelin.

The endogenous ligand for growth-hormone secretagogue receptor (GHS-R) was discovered in 1999 from stomach and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow”, since ghrelin stimulates growth hormone (GH) release from pituitary. In addition, ghrelin stimulates appetite and increases food intake by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Thus, ghrelin plays important roles for maintaining growth hormone release and energy homeostasis in vertebrates. The diverse functions of ghrelin raise the possibility of its clinical application for GH deficiency, eating disorder, gastrointestinal disease, cardiovascular disease, osteoporosis and aging, etc.


Biochemistry of Ghrelin
Ghrelin hormone composed of 28-amino acid peptide modified at its third residue, a serine (Ser3), by a middle-chain fatty acid, n-octanoicacid.The Ser3-acylation is necessary for its biological activity, especially the binding and activation of the ghrelinhormone receptor. Ghrelinhormonewas discovered in 1999 from stomach, practiced potentappetite and growth hormone releasing stimulating activities [1,2] (Figure 1).The name "ghrelin" is based on "ghre", which is the root ofthe word in the Indo-European primary languages of the word "grow", in reference to ghrelin hormone ability to induce growth hormone release. Both the precursors of rat and human ghrelin are consists of 117 amino acids. In these precursors, the active ghrelin sequence of 28 amino acids immediately follows the signal peptide. Ghrelin hormone(peptide hormone), serine 3 (Ser3) is n-octanoylated and this modification is necessary for ghrelin activity.The enzyme that catalyzes acyl adjustment in ghrelin has not yet been specified. GlobalismInclusion of n-octanoic acid has been suggested inamphibians, mammals, fish, andbirdsthat this putative enzyme is somewhat specific in its choice of medium-chain fatty acid substrates [3].

Mechanism of Action
Ghrelin emerged as the first circulating hunger hormone.
Ghrelin and Synthetic ghrelin imitative (the growth hormone secretagogues) increase fat massand increase eat the food [4,5].An action is practiced at the level of the hypothalamus.They activate the cells in the arcuate nucleus which include the orexigenic neuropeptide Y (NPY) neurons [6]. Ghrelin responsiveness of these nerve cells bothinsulinsensitiveand leptin [7]. Ghrelinhormone activates the mesolimbic cholinergic dopaminergic bonus link, a circuit that communicates the hedonic and reinforcing aspects of natural bonus, like food as well as addictive drugs like ethanol [8].

Facts of Ghrelin
Ghrelin consists of 28 amino acids that originate from 94 long precursors of amino acids (progerlin). The other products of Progrelin are; des-Gln14-ghrelin (27 ghrelin), C-ghrelin, and obestatin. Ghrelin stimulates CRH by stimulating NPY, which inhibits endogenous g aminobutyric acid (GABA) neurons thus releasing the ventricular CRH nucleus from inhibiting [10,11] (Figure   3).Ghrelinhormonesynthesised in the stomach reaches the ARC via the bloodstream and possibly other brain areas via an active transport through the blood-brain barrier. Ghrelin hormone synthesized in the periphery stimulates the vagal connections that have been shown to express GHS-R, and the vagal connections connect to the tractussolitarius nucleus in the brainstem which then connects with the hypothalamus.Ghrelin is locally synthesized in the hypothalamus and has direct links with the NPY / agoutibound protein and other hypothalamic cells.

Ghrelin is a Potent Stimulator of GH Release
It is one of the major signaling mechanisms the start of the meal [18]. thereby decreased food intake. Ghrelin, a hormone secreted from the stomach, activates AGRP-NPY neurons and motivate food intake. leptin receptor (LepR); neuropeptide receptor (Y1R) [19].

Ghrelin and Control of Energy Balance
Two groups of neurons in the arcuate nucleus are known by the neuropeptides that they coexpress, the Neuropeptide Y (NPY) and Agouti Related Protein (AgRP) Orexigenic Neurons as well as the Proopiomelanocortin (POMC) and Cocaine and Amphetamine Related Transcript (CART) Anorexigenic Neurons. These co expressing neurons they are differentially regulated by circulating adiposity signals, satiety signals, differentially activate second order neurons that control food intake and energy expenditure [19]. It stores (long term energy availability),orchestrate hormonal, autonomic responses via differential regulation of downstream neurons in the hypothalamus and other brain regions. Ghrelin activates AMPK in hepatocytes, promotes autophagy, motivate mitochondrial biogenesis, and induces mitochondrial FFA b-oxidation, and so on ameliorates hepatic triglyceride over accumulation [21].(A)ghrelin attenuates hepatic lipotoxicity by enhancing autophagy via restoration of the AMPK/mTOR signaling pathway [22]. The ghrelin autophagy axis is essential for survival in famine. Under fasting, fat depleted conditions, organismsactivate hepatic autophagy to perform gluconeogenesis andmaintain blood glucose levels. This process is mainly orchestrated by the action of GH [23].Under hunger,fat depleted conditions, GOAT knockout mice exhibit insufficientGHup regulation, a decline in hepatic autophagy, and lethal hypoglycemia [24] (B).A comprehensive screen based on in vivo delivery of arrayed cDNA libraries aimed at identifying tissue protective factors revealedStrong and specific expression of the ghrelin gene in cardiac and skeletal muscles after acute ischemia [25]. Transduction of the ghrelin gene into the heart rescues Cardiomyocytes from ROS accumulation and apoptosis, Restores heart function after myocardial infarction in an autophagy manner (C).Desacyl ghrelin also reduce ROS production, lowers tissue inflammation and reinforces insulin stimulated glucose uptake in skeletal muscle in an autophagy dependent manner [26]. 4.6.9. Ghrelin is Anti-Inflammatory [27][28][29][30]: It has been shown that ghrelin is able to exert anti-inflammatory actions by inhibiting the production of inflammatory cytokines.Ghrelin practice anti-inflammatory actions in inflammatory bowel disease, sepsis,pancreatitis, arthritis, and diabetic nephropathy [31][32][33][34][35][36][37][38][39].

Ghrelin role Proautophagic Properties in Cellular Homeostasis
Administration of ghrelin before the development of experimental pancreatitis improved pancreatic blood flow, Lower IL1 levels, and stimulated pancreatic cell proliferation [33]. In sepsis, ghrelin, via an upregulation of MAPK phosphatase 1, lowerNorepinephrine and TNF levels known to cause hepatocellular dysfunction and upregulation of Proinflammatory Cytokines [40]. Furthermore, organ blood flow is improved by ghrelin via an inhibition of NF-kB (Wu, et al.) and HMGB1 production by activated macrophages is inhibited by ghrelin [32].

Conclusion
Ghrelin is a peptide hormone that the stomach secretes primarily into the bloodstream, but other tissues have been shown to also synthesize it. Ghrelin can exert its effects through systemic or atomicin/ paracrine actions. The GHS-R1A receptor binds to acyl ghrelin and presumably mediates its biological effects. None the less, it is I realized that either GHSR1A homo-or heterodimmers

Conflicts of Interest
The authors report no conflicts of interest in this work.