VGF: A Novel Role for This Neuronal and Neuroendocrine Polypeptide in the Regulation of Energy Balance

Salton, Stephen R.J.; Ferri, Gian-Luca; Hahm, Seung; Snyder, Susan E.; Wilson, A. J. C.; Possenti, Roberta; Levi, Andrea

doi:10.1006/frne.2000.0199

Cited by 158 publications

(182 citation statements)

References 48 publications

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“…In addition, germline VGF-/-mice have a lean, hypermetabolic, and obesity resistant phenotype [32,33]. However, the vgf gene encodes a phylogenetically highly conserved precursor protein of 615 (human) and 617 (rat, mice) amino acids [43,61]. A major feature of VGF is the presence of specific sequence with basic amino acid residues that represent potential cleavage sites for proprotein convertases of the kexin/subtilisin-like serine proteinase family.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Although one group was identifying downstream targets of exercise, and the other was focused on gene expression changes that were common following elevation of two putative mediators of antidepressant efficacy, the identification of VGF by both suggests a point of convergence between exercise and antidepressant signaling. Note that VGF is widely expressed in neurons in the brain and is involved in maintaining organismal energy balance, as well as in mediating hippocampal synaptic activity (19)(20)(21).…”

Section: Discovery Of Vgf As a Mediator Of Antidepressant Responsesmentioning

confidence: 99%

VGF, a New Player in Antidepressant Action?

Malberg

Monteggia

2008

Sci. Signal.

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Recent studies have identified adaptations of intracellular signaling pathways and target genes that could contribute or modulate the action of antidepressant drugs, as well as exercise-mediated antidepressant responses. Understanding these adaptations, particularly those changes that are common to diverse antidepressant treatments, is important for the development of more potent and specific treatments of depression. There is growing evidence that growth factors may be important mediators of antidepressant responses. Now, VGF (not an acronym), a neuropeptide that has previously been shown to be involved in maintaining organismal energy balance, as well as in mediating hippocampal synaptic plasticity, may be involved in mediating antidepressant responses. These studies use in vivo approaches to link VGF to the antidepressant-like behavioral effects produced by antidepressant drugs and exercise.

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“…vgf gene expression is regulated in the brain in a region-specific manner by neuronal activity, brainderived neurotrophic factor, seizure, injury, long term potentiation, circadian rhythm, and fasting (11,12). Functional studies based on the analysis of VGF mutant mice indicate that the encoded protein plays a critical role in the control over feeding and energy expenditure (13,14).…”

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“…Functional studies based on the analysis of VGF mutant mice indicate that the encoded protein plays a critical role in the control over feeding and energy expenditure (13,14). VGF peptides have been identified in several endocrine organs including the pituitary and pancreas, as well as in the brain and cerebrospinal fluid (11). Recent studies have further demonstrated that expression of the vgf gene is induced in response to hippocampus-dependent learning paradigms, and that the C-terminal VGF peptides regulate hippocampal neuronal excitability (15).…”

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confidence: 99%

“…The ϳ68-kDa VGF polypeptide is relatively rich in proline and glutamic acid, contains a number of paired (di)basic residues, and is differentially processed in a cell type-specific manner in neuronal, neuroendocrine, and endocrine cells (11). This coupled with its localization in dense core secretory vesicles has suggested a similarity to the chromogranin/secretogranin family despite a lack of obvious similarities between their primary amino acid sequences.…”

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A Prohormone Convertase Cleavage Site within a Predicted α-Helix Mediates Sorting of the Neuronal and Endocrine Polypeptide VGF into the Regulated Secretory Pathway

Garcia

Han

Janssen

et al. 2005

Journal of Biological Chemistry

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Distinct intracellular pathways are involved in regulated and constitutive protein secretion from neuronal and endocrine cells, yet the peptide signals and molecular mechanisms responsible for targeting and retention of soluble proteins in secretory granules are incompletely understood. By using confocal microscopy and subcellular fractionation, we examined trafficking of the neuronal and endocrine peptide precursor VGF that is stored in large dense core vesicles and undergoes regulated secretion. VGF cofractionated with secretory vesicle membranes but was not detected in detergent-resistant lipid rafts. Deletional analysis using epitope-tagged VGF suggested that the C-terminal 73-amino acid fragment of VGF, containing two predicted ␣-helical loops and four potential prohormone convertase (PC) cleavage sites, was necessary and sufficient with an N-terminal signal peptide-containing domain, for large dense core vesicle sorting and regulated secretion from PC12 and INS-1 cells. Further transfection analysis identified the sorting sequence as a compact C-terminal ␣-helix and embedded 564 RRR 566PC cleavage site; mutation of the 564 RRR 566 PC site in VGF-(1-65): GFP:VGF-(545-617) blocked regulated secretion, whereas disruption of the ␣-helix had no effect. Mutation of the adjacent 567 HFHH 570 motif, a charged region that might enhance PC cleavage in acidic environments, also blocked regulated release. Finally, inhibition of PC cleavage in PC12 cells using the membrane-permeable synthetic peptide chloromethyl ketone (decanoyl-RVKR-CMK) blocked regulated secretion of VGF. Our studies define a critical RRR-containing C-terminal domain that targets VGF into the regulated pathway in neuronal PC12 and endocrine INS-1 cells, providing additional support for the proposed role that PCs and their cleavage sites play in regulated peptide secretion.Regulated secretion of polypeptides from neuronal and endocrine cells, which relies on packaging of proteins into the appropriate vesicle pools within the cell, is a critical control point for regulating peptide levels and ultimately function. Polypeptide motifs that target cell surface proteins to specific vesicle populations or to discrete locations within the cell, such as the basolateral or apical surface of a polarized epithelial cell, have been relatively well characterized (1). Protein domains that are responsible for targeting soluble proteins into the regulated release pathway appear to be more heterogeneous, and thus generalized sorting domains and consensus motifs have been more difficult to identify. Perhaps as a consequence, several models that explain targeting into the regulated secretory pathway by selective sorting and/or selective retention have been proposed (2-5). Following signal sequence-directed translocation into the lumen of the endoplasmic reticulum, segregation of proteins into the constitutive or regulated pathways is suspected to occur in the trans-Golgi network (TGN). 4 Constitutive secretory vesicles transit directly from the TGN to the plasma membran...

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VGF: A Novel Role for This Neuronal and Neuroendocrine Polypeptide in the Regulation of Energy Balance

Cited by 158 publications

References 48 publications

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

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

VGF, a New Player in Antidepressant Action?

A Prohormone Convertase Cleavage Site within a Predicted α-Helix Mediates Sorting of the Neuronal and Endocrine Polypeptide VGF into the Regulated Secretory Pathway

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