Genomic Structure and Characterization of the 5′-Flanking Region of the Human Ghrelin Gene

Kanamoto, Naotetsu; Akamizu, Takashi; Tagami, Tetsuya; Hataya, Yuji; Moriyama, Kenji; Takaya, Kazuhiko; Hosoda, Hiroshi; Kojima, Masayasu; Kangawa, Kenji; Nakao, Kazuwa

doi:10.1210/en.2003-1718

Cited by 76 publications

(80 citation statements)

References 63 publications

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“…Ghrelin, a 28-amino acid endogenous ligand for growth-hormone secretagogue receptor (GHSR) surges before mealtime (19)(20)(21). The numerous E-box elements, known targets of circadian clock proteins, present in the promoter region of the ghrelin gene (22) likely play a role in the timing of ghrelin synthesis. Furthermore, plasma levels of ghrelin fluctuate diurnally, with a peak in the day and a trough at night (23), and exogenous ghrelin administration stimulates eating (24).…”

mentioning

confidence: 99%

Stomach ghrelin-secreting cells as food-entrainable circadian clocks

LeSauter

Hoque

Weintraub

et al. 2009

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

281

269

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Increases in arousal and activity in anticipation of a meal, termed “food anticipatory activity” (FAA), depend on circadian food-entrainable oscillators (FEOs), whose locations and output signals have long been sought. It is known that ghrelin is secreted in anticipation of a regularly scheduled mealtime. We show here that ghrelin administration increases locomotor activity in nondeprived animals in the absence of food. In mice lacking ghrelin receptors, FAA is significantly reduced. Impressively, the cumulative rise of activity before food presentation closely approximates a Gaussian function ( r = 0.99) for both wild-type and ghrelin receptor knockout animals, with the latter having a smaller amplitude. For both groups, once an animal begins its daily anticipatory bout, it keeps running until the usual time of food availability, indicating that ghrelin affects response threshold. Oxyntic cells coexpress ghrelin and the circadian clock proteins PER1 and PER2. The expression of PER1, PER2, and ghrelin is rhythmic in light–dark cycles and in constant darkness with ad libitum food and after 48 h of food deprivation. In behaviorally arrhythmic-clock mutant mice, unlike control animals, there is no evidence of a premeal decrease in oxyntic cell ghrelin. Rhythmic ghrelin and PER expression are synchronized to prior feeding, and not to photic schedules. We conclude that oxyntic gland cells of the stomach contain FEOs, which produce a timed ghrelin output signal that acts widely at both brain and peripheral sites. It is likely that other FEOs also produce humoral signals that modulate FAA.

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mentioning

confidence: 99%

Stomach ghrelin-secreting cells as food-entrainable circadian clocks

LeSauter

Hoque

Weintraub

et al. 2009

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

281

269

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“…The human ghrelin gene is located on chromosome 3p25-26. It comprises five exons and three introns, being the short first exon only 20 bp long, which encode part of the 5 0 untranslated region [77,81]. Mature ghrelin (i.e., the 28-amino acid GH releasing peptide) is encoded by exons 2 and 3 with the remaining proghrelin peptide sequence contained in exons 4 and 5 [75].…”

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confidence: 99%

“…Additionally, multiple putative binding sites for transcription factors have been identified including AP2, basic helix-loop-helix (bHLH), PEA-3, Myb, NF-IL-6, hepatocyte nuclear factor-5, and NF-B, and half-sites for estrogen and glucocorticoid response elements [77,81].…”

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confidence: 99%

Ghrelin, des-acyl ghrelin and obestatin: Three pieces of the same puzzle

2008

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a b s t r a c tThe major active product of ghrelin gene is a 28-amino acid peptide acylated at the serine 3 position with an octanoyl group, called simply ghrelin. Ghrelin has a multiplicity of physiological functions, affecting GH release, food intake, energy and glucose homeostasis, This suggests the existence of a novel endocrine system with multiple effector elements which not only may have opposite actions but may regulate the action of each other. In this review, we summarize the steps which lead to the production of the different ghrelin gene products and examine the most significant differences between them in terms of structure and actions.

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“…List of mammalian neuroendocrine factors containing an E-box (CACGTG) enhancer in their promoter GnRH-I No (Hayflick et al, 1989) GnRH-II No (White et al, 1998) Ghrelin No (Kanamoto et al, 2004) Oxytocin No (Hara et al, 1990) Vasopressin Yes (1) (Hara et al, 1990;Jin et al, 1999) TRH No (Satoh et al, 1996) Pituitary:…”

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confidence: 99%

The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

129

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Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between "clock cells" and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized. KeywordsCircadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic Circadian aspects of reproductionThe importance of circadian (about a day) timing in hormone production/secretion has been known since the 1950s when Everett and Sawyer determined that a stimulatory signal occurring during a narrow temporal window on the afternoon of proestrus is necessary for induction of ovulation later that night (Everett and Sawyer, 1950). Such close temporal organization is important for successful reproduction, as numerous hormone-dependent behavioral and physiological processes must be coordinated. If optimal temporal relationships are disrupted, pronounced deficits in fertility can result. For example, ovulation, behavioral estrus, fertilization, and pregnancy maintenance require a specific

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Genomic Structure and Characterization of the 5′-Flanking Region of the Human Ghrelin Gene

Cited by 76 publications

References 63 publications

Stomach ghrelin-secreting cells as food-entrainable circadian clocks

Stomach ghrelin-secreting cells as food-entrainable circadian clocks

Ghrelin, des-acyl ghrelin and obestatin: Three pieces of the same puzzle

The regulation of neuroendocrine function: Timing is everything

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