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

Abstract

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.

Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice

“…In contrast, prevention of EEinduced Vgf up-regulation failed to attenuate the decrease of adiposity or Bdnf up-regulation, suggesting a minor role of VGF in the HSA axis, with respect to EE. Previous studies examined the effects of fasting on hypothalamic VGF expression by in situ hybridization (22,33,46). However, results have been varied and some are discrepant to our finding by quantitative reverse transcription PCR on block dissection of the hypothalamus.…”

“…It has been hypothesized that these contrasting findings are due to bioactive peptides derived from VGF peptide precursor having antagonistic functions, e.g., TLQP-21 is catabolic, whereas neuroendocrine regulatory peptide-2 is anabolic (31,32). Notably, VGF peptides have also shown heterogeneous expression in several neuroendocrine tissues including the stomach and pancreas (30,33). In addition, the compensatory responses during development may confound the germline knockout findings.…”

“…Furthermore, the results of our knockdown study are supportive to the findings that hypothalamic VGF was up-regulated by the HSA axis activation and often mirrored BDNF in the same regions of the hypothalamus. Vgf gene produces a peptide precursor that is further processed to generate several mature peptides with distinct functions (31,33). To add more complexity, 2 receptors have been identified that bind TLQP-21, the G protein-coupled complement 3a complement receptor (47), and the gC1q complement receptor (48), whereas whether other VGF-derived peptides act on distinct receptors remains unknown.…”

VGF: An inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers

“…Different VGF-peptide profiles were found in the rat and swine stomach (see Table 1, and Fig. 6, H-O panels: Brancia et al, 2010), in ghrelin, somatostatin, EC, ECL and other mucosal cell types, especially principal cells. The latter location appeared to parallel the presence of gastric leptin, as well as of other neuro-endocrine peptides (Bado et al, 1998;Susaki et al, 2005).…”

Neuropeptide TLQP-21, a VGF Internal Fragment, Modulates Hormonal Gene Expression and Secretion in GH3 Cell Line

“…TLQP-21 exerts a number of biological functions including: chronic i.c.v. infusion increases energy expenditure and prevents the early phase of diet-induced obesity [12], peripheral infusion induces prolipolytic effect [13], it regulates food intake and body weight in Syrian hamsters but not in mice [14,15], it regulates gastric functions in vitro and in vivo [16,17,18], and data report the modulation of this peptide by feeding in gastric endocrine cells [19]. TLQP-21 did not show any activity on GH expression and secretion in porcine pituitary slices in vitro [20] and in vivo after chronic TLQP-21 i.v.…”