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Ghrelin, Leptin and Obestatin Peptides Offered by Bachem

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Ghrelin, Leptin and Obestatin Peptides Offered by Bachem GHRELIN, LEPTIN AND OBESTATIN Ghrelin, Leptin and Obestatin GHRELIN, LEPTIN AND OBESTATIN PEPTIDES OFFERED BY BACHEM Ghrelin is an endogenous peptide discovered by Kojima et al. in 1999 during the search for an unknown endogenous ligand of a receptor of known structure and function. It is a 28 amino acid peptide with an essential n-octanoyl modification on the hydroxy group of Ser3. It displays strong growth hormone-releasing activity mediated by the growth hormone secretagogue receptor 1a (GHS- R1a). Ghrelin participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure by lower- ing the catabolism of fat. Several years after the isolation of ghre- lin a second peptide derived from preproghrelin was isolated from rat stomach. This 23 amino acid peptide named obestatin was ini- tially considered to oppose the orexigenic (appetite-stimulating) effects of ghrelin. It was also reported to be the cognate ligand for the G-protein-coupled receptor GPR39. Later studies, however, cast doubt on the initial findings as subsequent studies failed to confirm the anorexigenic effects of obestatin. Leptin, a satiety hor- mone produced by white adipose tissue, was discovered in 1994 and represents another appetite regulator. Leptin and ghrelin are supposed to share hypothalamic pathways regulating food intake and energy homeostasis. 2 Isolation of Ghrelin tion of ghrelin was discovered by Yang et al. Fig. 1. Studies on peptidyl growth hormone (GH) Ghrelin O-acyltransferase (GOAT) belongs Prepro-Ghrelin can be processed to ghrelin secretagogues (GHS), initially discovered by to the superfamily of membrane-bound and obestatin Bowers and Momany in 1976, led to the iden- O-acyltransferases (MBOATs). Human GOAT tification of the GHS receptor in 1996. is expressed in various tissues including The GHS receptor belongs to the family of G- stomach and pancreas and can also modify protein-coupled receptors containing seven ghrelin with other fatty acids such as dec- transmembrane (TM) domains and three anoate. intracellular and extracellular loops. Octanoylation of ghrelin is required for Despite intensive search by various groups, receptor binding and activation. Non- the endogenous ligand of the GHS receptor octanoylated ghrelin does not stimulate GH could not be isolated for a long time. Only secretion nor inhibit the activity of native synthetic ligands, such as growth hormone- ghrelin. Studies with synthetic ghrelin de- releasing peptide-6 (GHRP-6), or hexarelin rivatives indicated that the amino-terminal were known for this receptor. sequence Gly-Ser-Ser(octanoyl)-Phe-Leu The cloning of the GHS receptor in 1996 was appears to be the ‚core‘ structure necessary an important step towards the identifica- for ghrelin function. tion of the endogenous ligand. In 1999, a Interestingly, there is no structural homology Japanese group of scientists (Kojima et al.) between ghrelin and other growth hormone succeeded in the purification and identifica- secretagogues (GHRP-6 or hexarelin). tion of a peptide in rat stomach that could Non-acylated ghrelin is far more abundant stimulate the GHS receptor stably transfect- than acylated ghrelin and exists at signifi- ed into Chinese hamster ovary (CHO) cells. cant levels in both stomach and blood. The purified ligand was found to be a peptide Both acylated ghrelin and non-acylated of 28 amino acids, called ghrelin (‚ghre‘ is a ghrelin share some GHSR1a-independent word root in Proto-Indo-European languages, effects such as stimulation of lipid accumu- meaning ‚growth‘, the suffix ‚relin‘ indicates lation in human visceral adipocytes, inhibi- that a peptide is a releasing hormone). The tion of isoproterenol-induced lipolysis in rat side chain of serine in position 3 of ghrelin adipocytes, and inhibition of apoptosis in was demonstrated to be modified by an oc- cardiomyocytes and endothelial cells. tanoyl group. This unusual esterification has Recent studies indicate a role of ghrelin, des- not been described before. acyl ghrelin, and GOAT in glucose homeosta- By using the rat cDNA sequence for screen- sis. ing a human stomach cDNA library under low stringency conditions, the human ghrelin sequence was subsequently identified. Physiological Functions of Ghrelin The human ghrelin gene is localized on chro- mosome 3 at position p25-26 and comprises Regulation of growth hormone secretion five exons. Human ghrelin is derived from GH secretion from the pituitary gland is a 117 amino acid precursor (Fig. 1). Like its controlled primarily by two hypothalamic rat analog, the human peptide consists of peptides, growth hormone-releasing hor- 28 amino acids and is post-translationally mone (GHRH) (Bachem product H-3695) and modified with an octanoyl group on serine at somatostatin. With the isolation of ghrelin, position 3. It differs from the rat sequence in a third regulator of GH secretion has been two amino acids. discovered. In 2008, the enzyme catalyzing the O-acyla- Ghrelin acts as an antagonist of somatosta- Prepro-Ghrelin (human) 1 23 24 51 52 75 76 98 99 117 Ghrelin (human) Obestatin (human) 3 Ghrelin, Leptin and Obestatin tin that inhibits the secretion but not the the BBB is very low. Several studies sug- Fig. 2. synthesis of GH. Together with GHRH, ghrelin gested that the orexigenic signal of ghrelin Interrelationship of acts synergistically to stimulate the release secreted from the stomach is transmitted Ghrelin and Leptin. Activation of ghre- of GH from the somatotrophic cells of the to the brain via the vagal afferent nerve. This lin receptors causes hypophysis. was supported by the finding that vagotomy release of neuropeptide Amongst a range of tested neuropeptides inhibits the ability of ghrelin to stimulate Y (NPY) and agouti- only GHSs bound specifically to the GHS food intake. However, other studies con- related protein (AgRP) receptor. cluded that abdominal vagal afferents are thus stimulating hunger GHRH, somatostatin, and ghrelin mediate not required for the acute eating-stimulatory and food intake (orexi- their effects through G-protein-coupled effect of ghrelin. genic effect). Activa- tion of leptin receptors receptors. GHRH activates adenylyl cyclase, Ghrelin receptors are synthesized by a sub- increases expression cyclic AMP, and protein kinase A pathways, set of vagal afferent neurons of the nodose of proopiomelanocortin whereas ghrelin stimulates phospholipase ganglion and then transmitted to axon termi- (POMC), α-melanocyte- C activity leading to production of inositol- nals where they bind to ghrelin. Ghrelin can stimulating hormone 1,4,5-triphosphate and diacylglycerol, influence gastric satiety signaling by altering (α-MSH) and cocaine increase in cytosolic calcium levels, and the mechanosensitivity of gastric vagal af- and amphetamine-reg- GH release. Somatostatin acts through an ferents to distension. ulated transcript (CART) in the arcuate nucleus inhibitory G-protein-coupled receptor thus The ghrelin receptor is expressed in several (anorexigenic effect). blocking GH secretion. hypothalamic nuclei. Many of them are Leptin also inhibits the known to be involved in the regulation of food release of NPY and AgRP Influence of food intake and energy bal- intake and body weight. and prevents the sup- ance Ghrelin is also synthesized locally in neurons pressive effect of these Ghrelin not only stimulates GH secretion, it of hypothalamic areas such as the paraven- neurons on POMC/CART also increases food intake and weight gain in tricular and the arcuate nucleus but also in neurons. experimental animals and induces hunger in the sensorimotor area of the cerebral cortex humans. and in the cingulate gyrus. Ghrelin is part of a complex neuroendocrine In the arcuate nucleus, ghrelin-containing network involved in the regulation of appetite neurons send efferent fibers onto neu- and energy homeostasis. rons expressing neuropeptide Y (NPY) and Peripheral ghrelin may exert its effects on agouti-related protein (AgRP) to stimulate the CNS by crossing the blood brain barrier the release of these orexigenic peptides. (BBB) although the rate at which it passes This is complemented by a suppressive ef- Stomach Adipose Tissue Stomach Adipose Tissue Ghrelin Ghrelin Leptin Leptin GHS Receptor GHS Receptor Vagal Nerve Vagal Nerve Hypothalamus Hypothalamus Ghrelin Ghrelin Neurons Neurons Leptin Leptin GHS Receptor GABA GHS Receptor Leptin Receptor Leptin Receptor Leptin Receptor POMC/ POMC/ NPY/AgRP NPY/AgRP Neuron CART Neuron CART Neuron Neuron GABA Receptor GABA Receptor AgRP / NPY α-MSH / CART Orexigenic Effect Anorexigenic Effect 4 fect on proopiomelanocortin/cocaine- and tive axis in situations of energy deficit. amphetamine-regulated transcript (POMC/ CART)-expressing neurons via inhibitory γ-aminobutyric acid (GABA) inputs from NPY/ Identification of Leptin AgRP neurons. The hypothalamic NPY/Y1 Leptin has been discovered in 1994 by receptor pathway is shared by leptin. Ghrelin positional cloning of the mouse obese gene antagonizes the anorectic effect of leptin originally described in 1950. Mice which are through the activation of this pathway homozygous for the recessive obese muta- (Fig. 2). tion exhibit hyperphagia and increase rapidly in weight. The ob/ob phenotype is also char- Effects of ghrelin on the cardiovascular acterized by infertility and a form of diabetes system similar to human type-II diabetes. The mouse A study of the peripheral distribution of GHS obese gene was mapped to chromosome 6. It receptors has shown that ghrelin is also encodes
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