The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas

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Abstract

Objectives: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), was recently identified in the stomach. Ghrelin is produced in a population of endocrine cells in the gastric mucosa, but expression in intestine, hypothalamus and testis has also been reported. Recent data indicate that ghrelin affects insulin secretion and plays a direct role in metabolic regulation and energy balance. On the basis of these findings, we decided to examine whether ghrelin is expressed in human pancreas. Specimens from fetal to adult human pancreas and stomach were studied by immunocytochemistry, for ghrelin and islet hormones, and in situ hybridisation, for ghrelin mRNA. Results: We identified ghrelin expression in a separate population of islet cells in human fetal, neonatal, and adult pancreas. Pancreatic ghrelin cells were numerous from midgestation to early postnatally (10% of all endocrine cells). The cells were few, but regularly seen in adults as single cells at the islet periphery, in exocrine tissue, in ducts, and in pancreatic ganglia. Ghrelin cells did not express any of the known islet hormones. In fetuses, at midgestation, ghrelin cells in the pancreas clearly outnumbered those in the stomach. Conclusions: Ghrelin is expressed in a quite prominent endocrine cell population in human fetal pancreas, and ghrelin expression in the pancreas precedes by far that in the stomach. Pancreatic ghrelin cells remain in adult islets at lower numbers. Ghrelin is not co-expressed with any known islet hormone, and the ghrelin cells may therefore constitute a new islet cell type.

Introduction

Ghrelin, a novel peptide of 28 amino acids, was recently isolated from rat stomach as ligand of the growth hormone secretagogue receptor (GHS-R) [1]. Independently, Tomasetto et al. [2] discovered mRNA in the mouse stomach that encoded a novel protein of 117 amino acid residues with distant chemical relationship to the motilin precursor; it was named motilin-related peptide (MTLRP) and turned out to be the mouse homologue of preproghrelin. Ghrelin/MTLRP, further on called ghrelin, was found to be produced by a population of endocrine cells, which are most abundant in the oxyntic mucosa in the stomach, less frequent in the gastric antrum, and still fewer in the small intestine [3], [4]. Ghrelin has also been detected in hypothalamus [1], kidney [5], testis [6], and placenta [7]. It has been suggested that ghrelin, secreted primarily from the stomach, acts as a hormone to release GH from the pituitary [8]. Recent studies have shown additional actions of ghrelin. Ghrelin stimulates food intake when given either i.p. or intracerebroventricularly (i.c.v.) in rats [9], [10]. Ghrelin administered i.c.v. and s.c. in rats and mice causes body weight gain with increased adiposity through changes in energy balance, including a reduction in fat utilisation [10], [11]. Ghrelin stimulates gastric motility and acid secretion in rats [12]. Ghrelin mRNA is upregulated in the stomach, and plasma ghrelin levels are elevated upon fasting in rats [13]. Further, plasma ghrelin levels are elevated preprandially and reduced postprandially in humans [14], [15]. Interestingly, reduced levels of plasma ghrelin have been demonstrated in human obesity [16]. Thus, many recent data indicate that ghrelin is involved in metabolic regulation and energy balance, and it has become evident that certain ghrelin actions are independent of GH [10], [17]. Many of the peptides involved in metabolic regulation, e.g. neuropeptide Y (NPY), peptide YY (PYY), somatostatin, and galanin, are expressed in the pancreatic islets [18], [19]; some of them, e.g. NPY and PYY, are upregulated during islet development [20]. We therefore decided to examine the possibility of ghrelin expression in the developing and mature human pancreas, using immunocytochemistry and in situ hybridisation.

Section snippets

Tissue collection and preparation

Human specimens were collected during many years (starting 1975), according to then used ethical guidelines. Specimens from fetal (gestational age 15–26 weeks) (n=7), newborn (sudden infant death) (n=1), and adult (age range 35–75; n=8) pancreas, usually separate specimens from duodenal (head) and splenic (tail) portions, and from the stomach, were from legal abortions, surgical resections, and autopsies. The specimens were frozen, freeze-dried and fixed in formaldehyde (vapour or liquid) or

Fetuses and neonatal

Ghrelin-immunoreactive (IR) cells were quite numerous in the fetal and neonatal pancreas (Fig. 1A,B). At midgestation (18–22 weeks) and at birth, ghrelin-IR cells constituted 9% and 11% of all demonstrable islet cells, respectively (Table 2). The ghrelin-IR cells sometimes formed an almost continuous layer at the peripheral rim of the islets (Fig. 1A). Single ghrelin-IR cells were also seen in the epithelium of ducts. In the stomach, only very few ghrelin-IR cells were detected at midgestation

Discussion

In this study, we show that ghrelin is expressed in human islets from early gestation to adult. Importantly, the immunocytochemical results correspond closely to the data obtained by in situ hybridisation of ghrelin mRNA expression. The ghrelin cells do not express any of the known pancreatic hormones (insulin, glucagon, somatostatin, or PP) at any stage. Ghrelin cells may therefore constitute a new islet cell type. While this work was in progress, Date et al. [24] presented data indicating

Acknowledgements

Grant supports from: Swedish Medical Research Council (Project No. 4499), Swedish Diabetes Association, and the Novo Nordic, Påhlsson, and Gyllensternska Krapperup Foundations. We thank Eva Hansson, Karin Jansner, Ann-Christin Lindh, and Doris Persson for expert technical assistance.

References (42)

  • X.M. Guan et al.

    Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues

    Brain Res. Mol. Brain Res.

    (1997)
  • W. Zhang et al.

    Inhibition of pancreatic protein secretion by ghrelin in the rat

    J. Physiol.

    (2001)
  • M. Kojima et al.

    Ghrelin is a growth-hormone-releasing acylated peptide from stomach

    Nature

    (1999)
  • Y. Date et al.

    Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

    Endocrinology

    (2000)
  • M. Tena-Sempere et al.

    Novel expression and functional role of ghrelin in rat testis

    Endocrinology

    (2002)
  • O. Gualillo et al.

    Ghrelin, a novel placental-derived hormone

    Endocrinology

    (2001)
  • A.M. Wren et al.

    The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion

    Endocrinology

    (2000)
  • M. Tschöp et al.

    Ghrelin induces adiposity in rodents

    Nature

    (2000)
  • A.M. Wren et al.

    Ghrelin causes hyperphagia and obesity in rats

    Diabetes

    (2001)
  • M. Tschöp et al.

    Post-prandial decrease of circulating human ghrelin levels

    J. Endocrinol. Invest.

    (2001)
  • D.E. Cummings et al.

    A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes

    (2001)
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