Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans<sup>1</sup>

Date, Yukari; Kojima, Masayasu; Hosoda, Hiroshi; Sawaguchi, Akira; Mondal, Muhtashan S.; Suganuma, Tatsuo; Matsukura, Shigeru; Kangawa, Kenji; Nakazato, Masamitsu

doi:10.1210/endo.141.11.7757

Cited by 1,331 publications

(154 citation statements)

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“…5D), RQ was significantly decreased in the ghrl Ϫ/Ϫ mice compared with ghrl ϩ/ϩ littermates [ Fig. 5E; repeated measures ANOVA over entire time course, effect of genotype, F (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) ϭ 6.07, P ϭ 0.027]. A similar decrease in RQ was observed in the female mice (data not shown).…”

Section: Metabolic Rate and Fuel Preference Are Not Significantly Altsupporting

confidence: 58%

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Wortley

Anderson²,

García³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

413

325

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Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl ؊/؊ ) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl ؊/؊ mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl ؊/؊ mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.G hrelin is a 28-aa peptide produced predominantly in the stomach (1, 2) that has recently been identified as a ligand of the growth hormone (GH) secretogogue (GHS) receptor (GHS-R). Like other GHSs, activation of the receptor stimulates GH secretion from the pituitary gland (1). In addition to inducing GH release, administration of exogenous ghrelin also stimulates food intake and body weight gain (3-7), increases gastric motility and acid secretion (8, 9), and decreases lipid metabolism in mice and rats (3, 4). The effects of centrally administered ghrelin on food intake are independent of its ability to induce GH release and thought to result from its direct actions on the arcuate nucleus of the hypothalamus. Furthermore, recent studies have demonstrated that plasma ghrelin levels increase preceding meals and during fasting (10, 11). Thus, it has been suggested that ghrelin stimulates appetite and that inhibitors of endogenous ghrelin, therefore, could prove useful in reducing food intake and combating obesity (11).Supporting the possibility that ghrelin acts as a key regulator of appetite and food intake by actions on the hypothalamus, GHS-R is colocalized with neuropeptide Y (NPY)͞agouti-related protein (AgRP) neurons (12) in the arcuate nucleus, a region that is responsive to circulating peripheral nutrients and hormones and critically involved in the regulation of food intake (13). Indeed, ghrelin stimulates the spontaneous activity of these neurons (14), and central ghrelin administration increases NPY and AgRP gene expression (15). Moreover, ghrelin-immunoreactivity has been reported in the h...

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Section: Metabolic Rate and Fuel Preference Are Not Significantly Altsupporting

confidence: 58%

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Wortley

Anderson²,

García³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

413

325

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“…O. and 0.05% NaN 3 ) containing 0.5% normal rabbit serum. The anti-rat ghrelin-(1-11) or anti-rat ghrelin- (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) antisera were used at final dilutions of 1:6,000,000 and 1:20,000, respectively. After incubation for 12 h, 100 l of 125 I-labeled tracer (15,000 cpm) was added.…”

Section: Methodsmentioning

confidence: 99%

“…The ghrelin gene is abundantly expressed in rat (8) and human (14) stomach, and in the rat, no other major sources of ghrelin production have been observed (13,15). These results prompted us to question whether ghrelin should be drastically reduced following gastrectomy.…”

mentioning

confidence: 99%

Structural Divergence of Human Ghrelin

Hosoda¹,

Kojima²,

Mizushima³

et al. 2003

Journal of Biological Chemistry

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283

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Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser 3 , was isolated from rat stomach and found to be an endogenous ligand for the growthhormone secretagogue receptor (GHS-R). This octanoyl modification is essential for ghrelin-induced GH release. We report here the purification and identification of human ghrelin from the stomach, as well as structural analysis of the human ghrelin gene and quantitation of changes in plasma ghrelin concentration before and after gastrectomy. Human ghrelin was purified from the stomach by gel filtration and high performance liquid chromatography, using a ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a stable cell line expressing GHS-R to test the fractions. In the course of purification, we isolated human ghrelin of the expected size, as well as several other ghrelin-derived molecules. Classified into four groups by the type of acylation observed at Ser 3 ; these peptides were found to be non-acylated, octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All peptides found were either 27 or 28 amino acids in length, the former lacking the C-terminal Arg 28, and are derived from the same ghrelin precursor through two alternative pathways. The major active form of human ghrelin is a 28-amino acid peptide octanoylated at Ser 3 , as was found for rat ghrelin. Synthetic octanoylated and decanoylated ghrelins produce intracellular calcium increases in GHS-R-expressing cells and stimulate GH release in rats to a similar degree. Both ghrelin and the ghrelin-derived molecules were found to be present in plasma as well as stomach tissue. Plasma levels of immunoreactive ghrelin after total gastrectomy in three patients were reduced to approximately half of their pre-gastrectomy values, after which they gradually increased. This suggests that the stomach is the major source of circulating ghrelin and that other tissues compensate for the loss of ghrelin production after gastrectomy.

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“…Ghrelin is synthesized primarily by the stomach, and in substantially lower amounts by the bowel, pituitary, kidney, placenta, and hypothalamus (4,5). Accumulating evidence suggests that ghrelin contributes to the short-and long-term regulation of body weight as a key element of a complex central signaling network that regulates food intake and energy expenditure (6)(7)(8)(9).…”

mentioning

confidence: 99%

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity

Yildiz

Suchard

Wong

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

317

219

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Ghrelin plays a key role in the regulation of growth hormone secretion and energy homeostasis. Adiponectin is exclusively secreted by adipose tissue and is abundantly present in the circulation, with important effects on metabolism. We studied five lean and five obese young men [ages: 24.2 ؎ 1.0 (lean) and 21.8 ؎ 1.6 (obese) years (difference not significant); body mass indexes: 35.0 ؎ 1.3 and 23.0 ؎ 0.3 kg͞m 2 (P ‫؍‬ 0.01)], sampled blood every 7 min over 24 h, and measured ghrelin, adiponectin, and leptin in 2,070 samples for a total of 6,210 data points. Circulating 24-h ghrelin showed significant ultradian fluctuations and an orderly pattern of release in lean and obese subjects with similar pulsatility characteristics. Plasma adiponectin concentrations were significantly lower in the obese group, with lower pulse height. In contrast to leptin, which is secreted in an orderly manner, the 24-h patterns of adiponectin were not significantly different from random in both the lean and obese groups. We show here that adipocytes can simultaneously secrete certain hormones, such as leptin, in patterns that are orderly, whereas other hormones, such as adiponectin, are secreted in patterns that appear to be random. The cross-approximate entropy statistic revealed pattern synchrony among ghrelin-leptin, ghrelin-adiponectin, and leptinadiponectin hormone time series in the lean and obese subjects. Plasma ghrelin concentrations showed a nocturnal rise that exceeded the meal-associated increases in lean subjects, and this newly identified nocturnal rise was blunted in the obese. We suggest that the blunting of the nocturnal rise of ghrelin is a biological feature of human obesity.

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Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans¹

Cited by 1,331 publications

References 13 publications

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Structural Divergence of Human Ghrelin

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity

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Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans1

Cited by 1,331 publications

References 13 publications

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Structural Divergence of Human Ghrelin

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity

Contact Info

Product

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Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans¹