The Mitogenic and Antiapoptotic Actions of Ghrelin in 3T3-L1 Adipocytes

Kim, Min Seon; Yoon, Cho Ya; Jang, Pil Geum; Park, Young Joo; Shin, Chan Soo; Park, Hye Sun; Ryu, Je Won; Pak, Youngmi Kim; Park, Joong Yeol; Lee, Ki Up; Kim, Seong Yeon; Lee, Hong Kyu; Kim, Young–Bum; Park, Kyong Soo

doi:10.1210/me.2003-0459

Cited by 205 publications

(162 citation statements)

References 47 publications

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“…Ghrelin treatment of pre-adipocytes or motor neurons induced cellular prolifer- ation and differentiation into mature adipocytes or neurons [11,12,33]. While these findings suggest ghrelin may influence cell differentiation, proliferation, development or apoptosis, the mechanism by which ghrelin treatment exerts these effects is not clear.…”

Section: Discussionmentioning

confidence: 97%

“…Ghrelin gene expression is markedly higher in the fetal pancreas than in the stomach [10], suggesting ghrelin might be involved in the development, proliferation or differentiation of the pancreas. Ghrelin has been reported to possess mitogenic and anti-apoptotic actions in adipocyte cells; treatment of pre-adipocytes with ghrelin induced cellular proliferation and differentiation into mature adipocytes [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

et al. 2006

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Aims/hypothesis: Ghrelin, a stomach-derived hormone, functions in multiple biological processes, including glucose metabolism and cellular differentiation and proliferation. In this study, we examined whether early treatment with ghrelin can regenerate beta cells of the pancreas in an animal model of diabetes mellitus, the n0-STZ model, in which neonatal rats are injected with streptozotocin (STZ) at birth.Methods: Following administration of ghrelin to n0-STZ rats from postnatal days 2 to 8, we examined beta cell mass, mRNA expression levels of insulin and of pancreatic and duodenal homeobox 1 (Pdx1) gene, and pancreatic morphology on days 21 and 70. In addition, we investigated the effects of ghrelin on beta cell replication. Results: By day 21, ghrelin treatment increased pancreatic expression of insulin and Pdx1 mRNA in n0-STZ rats. The number of replicating cells was also significantly increased in the ghrelin-treated n0-STZ model. At day 70, n0-STZ rats exhibited hyperglycaemia, despite slight increases in plasma insulin levels. Ghrelin treatment resulted in the improvement of plasma glucose levels, which were associated with normal plasma insulin levels. Pancreatic insulin mRNA and protein levels were significantly increased in ghrelin-treated n0-STZ model animals. Conclusions/interpretation: These findings suggest that ghrelin promotes regeneration of beta cells in STZ-treated newborn rats. Thus, early administration of ghrelin may help prevent the development of diabetes in disease-prone subjects after beta cell destruction.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

et al. 2006

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“…Immunoblot analysis was conducted as previously described [20]. Forty-microgram samples of tissue lysate were separated by 8% SDS-PAGE and transferred to PVDF membranes.…”

Section: Western Blot Analysismentioning

confidence: 99%

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

et al. 2005

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Aims/hypothesis: Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia. Materials and methods: Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague-Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominant-negative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia. Results: Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and α2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses. Conclusions/ interpretation: Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counterregulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.

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“…At the functional level, n-octanoylated ghrelin treatment increases the rate of proliferation in a number of cell lines, including human prostate cancer (Jeffery et al 2002), HepG2 hepatoma (Murata et al 2002) and pancreatic adenocarcinoma cancer cell lines (Duxbury et al 2003), rodent pituitary tumour cells (Nanzer et al 2004), as well as some normal cell lines and primary cell cultures (Pettersson et al 2002, Andreis et al 2003, Kim et al 2004, Mazzocchi et al 2004, Zhang et al 2004b, Maccarinelli et al 2005. There is evidence to suggest that a similar system could exist in female hormone-dependent cancers, such as breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines

Jeffery

Murray²,

Yeh³

et al. 2005

Endocr Relat Cancer

111

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While oestrogen, progesterone and growth factors, including growth hormone (GH), are clearly implicated in the pathogenesis of breast cancer, there is now evidence that the newly described ghrelin axis is also involved. The aims of this study were to investigate the expression of the ghrelin axis in breast cancer tissues and cell lines and to examine the effect of ghrelin on breast cancer cell proliferation in vitro. Ghrelin and its functional receptor, the growth hormone secretagogue receptor (GHSR) type 1a, were expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHSR type 1b isoform was exclusively expressed in breast carcinoma, suggesting that it has potential as a diagnostic marker. Ghrelin treatment significantly increases the proliferation of the MDA-MB-435 and MDA-MB-231 breast cancer cell lines in vitro. In addition, we have described the expression of a human preproghrelin isoform, exon 3-deleted preproghrelin, which encodes mature ghrelin plus a novel C-terminal peptide. Quantitative RT-PCR was used to demonstrate that this mRNA isoform is highly expressed in the MDA-MB-435 metastatic breast cancer cell line relative to the benign MCF-10A breast epithelial cell line. The unique C-terminal peptide of exon 3-deleted preproghrelin is expressed in the glandular epithelium of breast cancer tissues, with high-grade carcinoma exhibiting the strongest immunoreactivity. The data presented here suggest that components of the ghrelin axis may represent novel markers for breast cancer and potential therapeutic targets.

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The Mitogenic and Antiapoptotic Actions of Ghrelin in 3T3-L1 Adipocytes

Cited by 205 publications

References 47 publications

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines

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