Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia

Rindi, Guido; Licini, Lisa; Necchi, Vittorio; Bottarelli, Lorena; Campanini, Nicoletta; Azzoni, Cinzia; Favret, M; Giordano, Giovanna; D'Amato, Filomena; Brancia, Carla; Solcia, Enrico; Ferri, Gian Luca

doi:10.1210/jc.2007-0035

Cited by 39 publications

(36 citation statements)

References 19 publications

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“…In the adrenal gland, PGH peptides were also present in a comparable profile of molecular forms; however, PGH immunoreactivity was broadly localised in the whole medulla, while TLQP peptides were confined to adrenalin cells (D'Amato et al 2008). The same or similar peptides were also found in human, in ECL tumour cells (Rindi et al 2007).…”

Section: Discussionmentioning

confidence: 74%

Selective expression of TLQP-21 and other VGF peptides in gastric neuroendocrine cells and modulation by feeding

Brancia¹,

Cocco²,

D'Amato³

et al. 2010

Journal of Endocrinology

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Although vgf gene knockout mice are hypermetabolic, administration of the VGF peptide TLQP-21 itself increased energy consumption. Agonist-antagonist roles are thus suggested for different VGF peptides, and the definition of their tissue heterogeneity is mandatory. We studied the rat stomach using antisera to C-or N-terminal sequences of known or predicted VGF peptides in immunohistochemistry and ELISA. TLQP (rat VGF 556-565 ) peptide/s were most abundant (162G11 pmol/g, meanGS.E.M.) and were brightly immunostained in enterochromaffin-like (ECL) cells and somatostatin cells. A peptide co-eluting with TLQP-21 was revealed in HPLC of gastric and hypothalamic extracts, while the extended TLQP-62 form was restricted to the hypothalamus. Novel PGH (rat VGF 422-430 ) peptide/s were revealed in ghrelin cells, mostly corresponding to low MW forms (0 . 8-1 . 5 kDa), while VGF C-terminus peptides were confined to neurons. VGF mRNA was present in the above gastric endocrine cell types, and was prominent in chief cells, in parallel with low-intensity staining for further cleaved products from the C-terminal region of VGF (HVLL peptides: VGF 605-614 ). In swine stomach, a comparable profile of VGF peptides was revealed by immunohistochemistry. When fed and fasted rats were studied, a clear-cut, selective decrease on fasting was observed for TLQP peptides only (162G11 vs 74G5 . 3 pmol/g, fed versus fasted rats, meanGS.E.M., P!0 . 00001). In conclusion, specific VGF peptides appear to be widely represented in different gastric endocrine and other mucosal cell populations. The selective modulation of TLQP peptides suggests their involvement in peripheral neuro-endocrine mechanisms related to feeding responses and/or ECL cell regulation.

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Section: Discussionmentioning

confidence: 74%

Selective expression of TLQP-21 and other VGF peptides in gastric neuroendocrine cells and modulation by feeding

Brancia¹,

Cocco²,

D'Amato³

et al. 2010

Journal of Endocrinology

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“…Of the various VGF antisera used, those against human and rat C-terminus proved highly species selective and were reserved to bovine/swine and rat tissues respectively, while HVLL and TLQP peptide antisera were used across species. The rat PGH antiserum worked well in immunohistochemistry in the three species tested here and in humans (Rindi et al 2007), hence was used throughout, except for ELISA of bovine and swine tissue extracts for which the human PGH antiserum was employed.…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, the abundance of PGH peptides throughout swine and bovine adrenaline as well as nor-adrenaline cells (and in fewer corresponding cells in the rat) suggests that such peptides may have a role in the secretory repertoire of both cell types. PGH peptides share a common sequence and apparent abundance in the adrenal between at least bovine and human, both species also showing intermediate-high MW adrenal PGH peptides encompassing more or less extended domains towards the VGF N-terminus (Rindi et al 2007).…”

Section: Discussionmentioning

confidence: 98%

“…In western blot of rat adrenal extracts, a rat VGF C-terminus (VGF 609-617 ) antiserum revealed intact VGF, but little low MW forms (Trani et al 1995). In humans, an immunocytochemical study using human VGF C-terminus and rat VGF 422-430 antisera showed labelled medullary cells from the tenth week of gestation, as well as in adult adrenal and its medullary tumours (Rindi et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Differential distribution of VGF-derived peptides in the adrenal medulla and evidence for their selective modulation

D'Amato

Noli

Brancia

et al. 2008

Journal of Endocrinology

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While vg f gene knockout mice are hyperactive and hypermetabolic, surprisingly the TLQP-21 brain VGF peptide increased energy consumption, suggesting that opposing regulatory effects could be exerted by peptides alternatively cleaved from the VGF precursor. Using antisera to the VGF precursor C-terminus and three cleavage products, we revealed a distinct differential distribution in adrenal, certain peptides (VGF [422][423][424][425][426][427][428][429][430] : PGH peptides) being found throughout bovine and swine medulla, while C-terminus and TLQP peptides were confined to adrenaline cells in the above species and in rat and C-terminally shortened forms (VGF 604-612 : HVLL peptides) to nor-adrenaline cells. Random abattoir samples of bovine and swine adrenal contained 520G40 and 450G60 pmol/g (meanGS.E.M. respectively) of C-terminus peptides and similar or lower amounts of others.Upon gel chromatography, bona fide VGF precursor,~7 . 5 and~3. 5 kDa forms were revealed by C-terminus assays, HVLL peptides being limited to small fragments. TLQP peptides included~7 . 5 kDa form and peaks accounting for TLQP-21 and predicted TLQP-30 and TLQP-42. Low molecular weight (MW) PGH peptides were revealed, together with a high MW form possibly encompassing the VGF precursor N-terminus. In acutely stressed swine, a striking increase was seen for C-terminus and TLQP peptides, with no significant differences for PGH peptides. A similar response was found in rat TLQP peptides showing a major increase upon an acute swimming stress and 30 min thereafter. A differential processing of the VGF precursor encompassing many areas of its primary sequence and selective modulations of its derived peptides occur in adrenal medullary cells, possibly relevant to adaptive homeostatic responses.

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“…No receptor has been so-far described for TLQP-21 and no reliable biochemical assay has been developed to detect TLQP-21; therefore, we still do not know where the peptide is expressed in the brain and where it exerts its functions (although some recent development has been obtained in peripheral immunoreactivity of VGF-peptides [19,57] and with other VGF-derived peptides [16]). However, according to the previous studies [7,37], TLQP-21 exerted its catabolic effects independently of any gene expression change in the hypothalamus thus allowing the conclusion that the site(s) of TLQP-21 activity lies downstream of the hypothalamic circuits.…”

Section: Discussionmentioning

confidence: 99%

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

et al. 2009

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The vgf gene regulates energy homeostasis and the VGF-derived peptide TLQP-21 centrally exerts catabolic effects in mice and hamsters. Here, we investigate the effect of chronic intracerebroventricular (icv) injection of TLQP-21 in mice fed high fat diet (HFD). Fast weightgaining mice injected with the peptide or cerebrospinal fluid were selected for physiological, endocrine, and molecular analysis. TLQP-21 selectively inhibited the increase in body weight and epididymal white adipose tissue (eWAT) weight induced by HFD in control animals despite both groups having a similar degree of hyperphagia. TLQP-21 normalized the increase in leptin and decrease in ghrelin while increasing epinephrine and epinephrine/norepinephrine ratio when compared to values in controls. Finally, HFD-TLQP-21 mice showed a selective increase of eWAT b3-adrenergic receptor mRNA. Peroxisome-proliferatoractivated-receptor-d and hormone-sensing-lipase mRNA were also upregulated. In conclusion, chronic icv infusion of TLQP-21 prevented the early phase of diet-induced obesity despite overfeeding. These effects were paralleled by activation of catabolic pathways within the eWAT. Our results further support a role for TLQP-21 as a catabolic neuropeptide.

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Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia

Abstract: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.

Cited by 39 publications

References 19 publications

Selective expression of TLQP-21 and other VGF peptides in gastric neuroendocrine cells and modulation by feeding

Selective expression of TLQP-21 and other VGF peptides in gastric neuroendocrine cells and modulation by feeding

Differential distribution of VGF-derived peptides in the adrenal medulla and evidence for their selective modulation

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

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