Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: Analysis of "humanized" knockin mice expressing full-length or truncated VGF

Masato Sadahiro, Connor Erickson, Wei Jye Lin, Andrew C. Shin, Maria Razzoli, Cheng Jiang, Samira Fargali, Allison Gurney, Kevin A. Kelley, Christoph Buettner, Alessandro Bartolomucci, Stephen R. Salton

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Targeted deletion of VGF, a secreted neuronal and endocrine peptide precursor, produces lean, hypermetabolic, and infertile mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes. Previous studies suggest that VGF controls energy expenditure (EE), fat storage, and lipolysis, whereas VGF C-terminal peptides also regulate reproductive behavior and glucose homeostasis. To assess the functional equivalence of human VGF1-615 (hVGF) and mouse VGF1-617 (mVGF), and to elucidate the function of the VGF C-terminal region in the regulation of energy balance and susceptibility to obesity,wegenerated humanized VGF knockin mouse models expressing full-length hVGF or a C-terminally deleted human VGF1-524 (hSNP), encoded by a single nucleotide polymorphism (rs35400704). We show that homozygous male and female hVGF and hSNP mice are fertile. hVGF female mice had significantly increased body weight compared with wild-type mice, whereas hSNP mice have reduced adiposity, increased activity- and nonactivity-related EE, and improved glucose tolerance, indicating thatVGFC-terminal peptides are not required for reproductive function, but 1 or more specific VGF C-terminal peptides are likely to be critical regulators of EE. Taken together, our results suggest that human and mouse VGF proteins are largely functionally conserved but that species-specific differences in VGF peptide function, perhaps a result of known differences in receptorbindingaffinity, likely alterthemetabolicphenotypeofhVGFcomparedwithmVGFmice,and in hSNP mice in which several C-terminal VGF peptides are ablated, result in significantly increased activity- and nonactivity-related EE.

Original languageEnglish (US)
Pages (from-to)1724-1738
Number of pages15
JournalEndocrinology
Volume156
Issue number5
DOIs
StatePublished - May 1 2015

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