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GHRELIN, AND OBESTATIN , Leptin and Obestatin

GHRELIN, LEPTIN AND OBESTATIN OFFERED BY BACHEM

Ghrelin is an endogenous discovered by Kojima et al. in 1999 during the search for an unknown endogenous ligand of a of known structure and function. It is a 28 peptide with an essential n-octanoyl modification on the hydroxy group of Ser3. It displays strong growth -releasing activity mediated by the secretagogue receptor 1a (GHS- R1a). Ghrelin participates in the regulation of , 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 . 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--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 , 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). 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 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 (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 . 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 Amongst a range of tested 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 -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 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 and induces hunger in the sensorimotor area of the cerebral cortex . 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 (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

Ghrelin Ghrelin Neurons Neurons

Leptin Leptin

GHS Receptor GABA GHS 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 a 167 amino acid protein containing present in cardiovascular tissue, which has a 21 amino acid signal sequence. The gene led to the exploration of the cardiovascular product was called leptin, after the Greek functions of ghrelin and synthetic growth word leptos meaning thin. Human leptin also hormone-releasing peptides. These ligands consist of 167 amino acids and is 83% simi- have several cardiovascular activities, lar to the mouse protein. The human gene including a cardioprotective effect against resides on chromosome 7. myocardial ischemia, and vasoactive and In 1995 the leptin receptor (Ob-R) was cardioprotective effects in both experimental identified. It is a single membrane-spanning models and humans. There is evidence that receptor and belongs to the class I cyto- certain cardioprotective effects are medi- kine receptor superfamily. The receptor is ated via a novel, yet to be identified cardiac encoded by the diabetes (db) gene. Mice receptor distinct from the GHS receptor. deficient for the leptin receptor (db/db mice) This is supported by the finding that both serve as a model for obesity, diabetes, and octanoylated and non-acylated ghrelin ex- dyslipidemia. Both human and mouse leptin hibited antiapoptotic effects on cardiomyo- receptors exist in several isoforms generated cytes which do not express the GHS receptor. by alternative splicing and can be divided Both ghrelin and non-acyl ghrelin, recognize into three classes: secreted, short, and long. a common high affinity binding site, although only the fatty acid modified form of ghrelin binds to the GHS receptor. Physiological Functions of Leptin

The role of the ghrelin in reproduction Regulation of food intake and body weight Ghrelin is also supposed to be involved in the Leptin acts as a satiety hormone. It is mainly regulation of reproductive function by acting secreted by white adipose tissue and its se- at central and peripheral levels. Ghrelin has rum levels positively correlate with the per- been described to predominantly nega- centage of body fat. Leptin signaling is part tively modulate the hypothalamic-pituitary- of a feedback mechanism controlling food gonadal (HPG) axis. Recently, intake and energy homeostasis. Interestingly, (KiSS-1) and its G-protein-coupled receptor elevated leptin serum levels are associated GPR54 (KiSS-1R) have been identified as with leptin resistance in obese subjects. an essential component of the HPG axis Leptin exerts its effects by binding to its controlling gonadotrophin secretion. Ghrelin receptor expressed in the brain and in pe- has been demonstrated to decrease KiSS-1 ripheral tissues. The long form of the leptin mRNA expression in the medial preoptic receptor (Ob-Rb), highly expressed in the hy- area without affecting GPR54 levels. pothalamus, is supposed to mediate most of At peripheral levels, ghrelin may also func- effects. Leptin signals via the Janus tion in the direct control of follicular develop- Kinase / Signal Transducer and Activator of ment, ovarian functions, and embryonal Transcription (JAK/STAT) pathway but also development. In addition, ghrelin has been modulates a number of other signaling path- suggested to influence the male reproduc- ways in the brain, such as the PI 3-kinase,

5 Ghrelin, Leptin and Obestatin

MAPK, and mTOR pathway. stomach, intestine, and hypothalamus. In the hypothalamus leptin inhibits neuro- Subsequent studies, however, failed to con- nal pathways that stimulate food intake by firm the anorexigenic effect of obestatin and counteracting the orexigenic effects of NPY/ activation of GPR39 and thereby questioned AgRP neurons and by activating anorexigenic the role of obestatin as cognate ligand for POMC/CART neurons. GPR39. The controversy about this peptide as a regulator of appetite still exists as the The role of the leptin in reproduction differences in the experimental findings Leptin is also involved in the regulation of could not be explained by methodological reproductive development and function by variations. indirectly influencing GnRH neuron activ- Obestatin has been reported to have ad- ity. Leptin signaling is part of a complex ditional roles such as the inhibition of thirst neuronal network which involves NPY/AgRP, and the regulation of memory, anxiety, and POMC/CART, and kisspeptin-1 neurons. As sleep. It has also been shown to stimulate the kisspeptin-1 neurons express leptin re- the proliferation of human retinal cells and ceptors, they may participate in transmitting to promote the survival of pancreatic β-cells metabolic information to the GnRH neurons. and human islets (and to induce the expres- Loss of KiSS-1 peptide or its receptor, sion of genes involved in the regulation of GPR54, results in hypothalamic hypogonad- β-cell mass and function). Additionally, it ism and infertility. may have functions in the regulation of adi- pocyte metabolism and adipogenesis.

Identification of Obestatin Prospects Obestatin was identified by Zhang et al. in The increasing prevalence of obesity is a 2005 on the basis of bioinformatic searches global problem. Body weight is regulated by of putative derived from the pre- complex mechanisms involving peptide hor- propeptides of known peptide hormones. mones produced in the brain and gut. Obestatin was predicted to be derived from The discovery of ghrelin and its receptor a conserved region of preproghrelin that was represents a milestone in understanding the flanked by potential convertase cleavage complex mechanisms involved in appetite sites. Based on this information the peptide regulation and energy homeostasis, gas- was subsequently isolated from rat stomach. trointestinal function, and growth. Ghrelin Obestatin consists of 23 amino acid and is represents a major component of a neuroen- C-terminally amidated. docrine network. It acts at several levels and regulates food intake and energy balance. The function of obestatin is less clearly de- Physiological Functions of Obestatin fined. Further studies are required to recon- cile the controversial results concerning the Influence on food intake physiological role of obestatin in opposing The newly discovered gastric peptide was the effects of ghrelin. initially shown to oppose the effects of ghre- As ghrelin is both orexigenic and adipogenic, lin by decreasing appetite and weight gain. the ghrelin system is an ideal therapeutic For this reason it was named obestatin (from target for the treatment of anorexia, cachex- the Latin word ‚obedere‘, meaning ‚to devour‘, ia, and obesity. Ghrelin’s cardioactive effects and ‚statin‘, denoting suppression). Similar will possibly allow the development of new to ghrelin, which requires posttranslational treatment options for chronic failure. modification by acylation, the biological ac- Leptin acts as a satiety hormone; but it is tivity of obestatin depended on modification also involved in regulation of reproductive by C-terminal amidation. functions like ghrelin. Detailed knowledge of Zhang et al. (1994) showed that obestatin the molecular processes underlying these binds to and activates the orphan receptor mechanisms will help to better understand GPR39. This G-protein-coupled receptor has the relationship between metabolism and been mapped to human chromosome 2 and reproduction. is expressed in multiple tissues, including

6 REFERENCES

A.M. Ingalls et al. T.L. Horvath et al. F. Broglio et al. Obese, a new mutation in the house Ghrelin and the regulation of energy Non-acylated ghrelin does not pos- mouse. balance - a hypothalamic perspec- sess the pituitaric and pancreatic J. Hered. 41, 317-318 (1950) tive. endocrine activity of acylated ghrelin C.Y. Bowers et al. 142, 4163-4169 in humans. Effects of the enkephalins and (2001) J. Endocrinol. Invest. 26, 192-196 enkephalin analogs on release of M. Kojima et al. (2003) pituitary hormones in vitro. Purification and distribution of ghre- M.A. Cowley et al. Mol. Endocrinol. 1, 287-292 (1977) lin: the natural endogenous ligand The distribution and mechanism of Y. Zhang et al. for the growth hormone secreta- action of ghrelin in the CNS demon- Positional cloning of the mouse gogue receptor. strates a novel hypothalamic circuit obese gene and its human homo- Horm. Res. 56 Suppl. 1, 93-97 (2001) regulating energy homeostasis. logue. M. Kojima et al. Neuron 37, 649-661 (2003) Nature 372, 425-432 (1994) Ghrelin: discovery of the natural M.A. Lazarczyk et al. L.A. Tartaglia et al. endogenous ligand for the growth Ghrelin: a recently discovered gut- Identification and expression clon- hormone secretagogue receptor. brain peptide (review). ing of a leptin receptor, OB-R. Trends Endocrinol. Metab. 12, 118- Int. J. Mol. Med. 12, 279-287 (2003) Cell 83, 1263-1271 (1995) 121 (2001) B. Holst et al. R.V. Considine et al. W.A. Banks et al. Common structural basis for consti- Serum immunoreactive-leptin con- Extent and direction of ghrelin tutive activity of the ghrelin receptor centrations in normal-weight and transport across the blood-brain family. obese humans. barrier is determined by its unique J. Biol. Chem. 279, 53806-53817 N. Engl. J. Med. 334, 292-295 (1996) primary structure. (2004) D.L. Foster and S. Nagatani J. Pharmacol. Exp. Ther. 302, 822- G. Muccioli et al. Physiological perspectives on leptin 827 (2002) Ghrelin and des-acyl ghrelin both as a regulator of reproduction: role G. Muccioli et al. inhibit isoproterenol-induced lipoly- in timing puberty. Neuroendocrine and peripheral sis in rat adipocytes via a non-type Biol. Reprod. 60, 205-215 (1999) activities of ghrelin: implications in 1a growth hormone secretagogue M. Kojima et al. metabolism and obesity. receptor. Ghrelin is a growth-hormone-releas- Eur. J. Pharmacol. 440, 235-254 Eur. J. Pharmacol. 498, 27-35 (2004) ing acylated peptide from stomach. (2002) D. Cocchi et al. Nature 402, 656-660 (1999) E.E. Muller et al. GH-releasing peptides and bone. I.E. Messinis and S.D. Milingos GH-related and extra-endocrine ac- J. Endocrinol. Invest. 28 (Suppl. 8), Leptin in human reproduction. tions of GH secretagogues in aging. 11-14 (2005) Hum. Reprod. Update 5, 52-63 (1999) Neurobiol. Aging 23, 907-919 (2002) A.P. Davenport et al. M.A. Bednarek et al. C.B. Saper et al. International union of pharmacology. Structure - function studies on the The need to feed: homeostatic and LVI. Ghrelin receptor nomenclature, new growth hormone-releasing hedonic control of eating. distribution, and function. peptide, ghrelin: Minimal sequence Neuron 36, 199-211 (2002) Pharmacol. Rev. 57, 541-546 (2005) of ghrelin necessary for activation O. Ukkola and S. Pöykkö F. Lago et al. of growth hormone secretagogue Ghrelin, growth and obesity. Ghrelin, the same peptide for differ- receptor 1a. Ann. Med. 34, 102-108 (2002) ent functions: player or bystander? J. Med. Chem. 43, 4370-4376 (2000) S.H. Bates et al. Vitam. Horm. 71, 405-432 (2005) R.R. Gonzalez et al. STAT3 signalling is required for R. Nogueiras and M. Tschöp Leptin and reproduction. leptin regulation of energy balance Biomedicine. Separation of con- Hum. Reprod. Update 6, 290-300 but not reproduction. joined hormones yields appetite (2000) Nature 421, 856-859 (2003) rivals. Science 310, 985-986 (2005)

7 Ghrelin, Leptin and Obestatin

T.L. Peeters B. Holst et al. T.A. Dardeno et al. Ghrelin: a new player in the control GPR39 signaling is stimulated by Leptin in human physiology and of gastrointestinal functions. zinc ions but not by obestatin. therapeutics. Gut 54, 1638-1649 (2005) Endocrinology 148, 13-20 (2007) Front. Neuroendocrinol. 31, 377-393 R.G. Smith et al. W.K. Samson et al. (2010) Developments in ghrelin biology and Obestatin acts in brain to inhibit D. Israel and S. Chua, Jr. potential clinical relevance. thirst. Leptin receptor modulation of adi- Trends Endocrinol. Metab. 16, 436- Am. J. Physiol. Regul. Integr. Comp. posity and fertility. 442 (2005) Physiol. 292, R637-643 (2007) Trends Endocrinol. Metab. 21, 10-16 A.D. Strader and S.C. Woods H.R. Berthoud (2010) Gastrointestinal hormones and food The vagus nerve, food intake and T. Kelesidis et al. intake. obesity. Narrative review: the role of leptin in Gastroenterology 128, 175-191 Regul. Pept. 149, 15-25 (2008) human physiology: emerging clinical (2005) R. Granata et al. applications. M. Tena-Sempere Obestatin promotes survival of pan- Ann. Intern. Med. 152, 93-100 (2010) Ghrelin: novel regulator of gonadal creatic beta-cells and human islets R. Granata et al. function. and induces expression of genes Cardiovascular actions of the ghrelin J. Endocrinol. Invest. 28, 26-29 involved in the regulation of beta- gene-derived peptides and growth (2005) cell mass and function. hormone-releasing hormone. J.V. Zhang et al. Diabetes 57, 967-979 (2008) Exp. Biol. Med. (Maywood) 236, 505- Obestatin, a peptide encoded by the L. Jiang et al. 514 (2011) ghrelin gene, opposes ghrelin’s ef- Leptin stimulates both JAK2-depen- U. Gurriaran-Rodriguez et al. fects on food intake. dent and JAK2-independent signal- Obestatin as a regulator of adipo- Science 310, 996-999 (2005) ing pathways. cyte metabolism and adipogenesis. M. Arnold et al. J. Biol. Chem. 283, 28066-28073 J. Cell. Mol. Med. 15, 1927-1940 Gut vagal afferents are not neces- (2008) (2011) sary for the eating-stimulatory J. Yang et al. K.M. Heppner et al. effect of intraperitoneally injected Identification of the acyltransferase The ghrelin O-acyltransferase- ghrelin in the rat. that octanoylates ghrelin, an appe- ghrelin system: a novel regulator of J. Neurosci. 26, 11052-11060 (2006) tite-stimulating . glucose metabolism. J.P. Camina Cell 132, 387-396 (2008) Curr. Opin. Endocrinol. Diabetes Cell biology of the ghrelin receptor. M.G. Myers et al. Obes. 18, 50-55 (2011) J. Neuroendocrinol. 18, 65-76 (2006) Mechanisms of leptin action and M.D. Li J.M. Cao et al. leptin resistance. Leptin and beyond: an odyssey to the Effects of ghrelin and synthetic GH Annu. Rev. Physiol. 70, 537-556 central control of body weight. secretagogues on the cardiovascu- (2008) Yale J. Biol. Med. 84, 1-7 (2011) lar system. E.C. Villanueva and M.G. Myers, Jr. C.T. Lim et al. Trends Endocrinol. Metab. 17, 13-18 Leptin receptor signaling and the The ghrelin/GOAT/GHS-R system (2006) regulation of mammalian physiology. and energy metabolism. M.J. Kleinz et al. Int. J. Obes. (Lond) 32 Suppl 7, S8-12 Rev. Endocr. Metab. Disord. 12, 173- Functional and immunocytochemi- (2008) 186 (2011) cal evidence for a role of ghrelin and F. Cordido et al. G.J. Morton and M.W. Schwartz des-octanoyl ghrelin in the regula- Ghrelin and growth hormone secre- Leptin and the central nervous sys- tion of vascular tone in man. tagogues, physiological and phar- tem control of glucose metabolism. Cardiovasc. Res. 69, 227-235 (2006) macological aspect. Physiol. Rev. 91, 389-411 (2011) N. Chartrel et al. Curr. Drug Discov. Technol. 6, 34-42 T. Sato et al. Comment on “Obestatin, a peptide (2009) Structure, regulation and function of encoded by the ghrelin gene, oppos- A. Rodriguez et al. ghrelin. es ghrelin’s effects on food intake”. Acylated and desacyl ghrelin stimu- J. Biochem. 151, 119-128 (2012) Science 315, 766; author reply 766 late lipid accumulation in human S. Kentish et al. (2007) visceral adipocytes. Diet-induced adaptation of vagal Int. J. Obes. (Lond) 33, 541-552 afferent function. (2009) J. Physiol. 590, 209-221 (2012)

8 GHRELIN, LEPTIN, OBESTATIN AND RELATED PRODUCTS Bachem also offers a range of products related to obesity research such as peptides, CART fragments, growth hormone releasing factors, neuropeptide Y and analogs, and . For more information, please see our online shop at shop.bachem.com

9 Ghrelin, Leptin and Obestatin

Ghrelin (human) Ghrelin (mouse, rat) H-4864 H-4862 GSS(octanoyl)FLSPE GSS(octanoyl)FLSPE HQRVQQRKESKKPPAKLQPR HQKAQQRKESKKPPAKLQPR

Ghrelin-Cys(BMCC-biotinyl) (human) (Des-octanoyl)-Ghrelin (mouse, rat) H-6334 H-6264 GSS(octanoyl)FLSPEHQRVQQRK GSSFLSPEHQKAQQRKESKKPPAK ESKKPPAKLQPRC(BMCC-biotinyl) LQPR

(Des-octanoyl)-Ghrelin (human) (Ser(Ac)³)-Ghrelin (mouse, rat) H-7746 H-7638 GSSFLSPEHQRVQQRKESKKPPAKLQPR GSS(acetyl)FLSPEHQKAQQRKESKKP- PAKLQPR (Des-octanoyl)-Ghrelin (human) H-5946 (D-Arg1,D-Phe5,D-Trp7·9,Leu11)-Sub- GSSFLSPEHQRVQQRKESKKPPAK stance P LQPR H-6935

rPKPfQwFwLL-NH2 ([¹³C₆]Leu⁵)-Ghrelin (human) H-7252 13 GSS(octanoyl)F[ C6]LSPE HQRVQQRKESKKPPAKLQPR

(Trp3,Arg5)-Ghrelin (1-5) H-6456 GSWFR

Obestatin (human) Obestatin (rat) OBESTATINS H-6356 H-6338 FNAPFDVGIKLSGVQYQQHSQAL-NH2 FNAPFDVGIKLSGAQYQQHGRAL-NH2

Biotinyl-Obestatin (human) Biotinyl-Obestatin (rat) H-6358 H-6362 Biotinyl-FNAPFDVGIKLSGVQYQQHSQAL- Biotinyl-FNAPFDVGIKLSGAQYQQHGRAL-

NH2 NH2

10 LEPTIN Leptin (22-56) (human) Leptin (126-140) (human) H-3424 H-3492 VPIQKVQDDTKTLIKTIVTRINDISHTQS- ETLDSLGGVLEASGY VSSKQK Leptin (138-167) (human) Tyr-Leptin (26-39) (human) H-3428 H-3494 SGYSTEVVALSRLQGSLQDMLWQLDL- YKVQDDTKTLIKTIV SPGC

Leptin (93-105) (human) Leptin (150-167) (human) H-3426 H-3432 NVIQISNDLENLR LQGSLQDMLWQLDLSPGC

Leptin (116-130) amide (mouse) rec Leptin (human) H-3966 H-5578

SCSLPQTSGLQKPES-NH2 rec Leptin (mouse) H-5582

GHRP-6 (D-Trp7,Ala8,D-Phe10)-α-MSH (6-11) amide H-9990

HwAWfK-NH2

LEPTIN MOLECULE Computer model showing the structure of a molecule of the hormone leptin. Leptin is produced by adipose (fat) tissue. It interacts with receptors in the brain’s hypothalamus to signal when a person is full. It also circulates in the blood at levels proportionate to body fat, which allows the brain to regulate appetite and metabolism. Mutations in the ob gene that codes for leptin are thought to be responsible for some forms of obesity.

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2003096 published by Global Marketing, Bachem Group, January 2017