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Endocrinology. 2015 May;156(5):1724-38. doi: 10.1210/en.2014-1826. Epub 2015 Feb 12.

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

Author information

1
Departments of Neuroscience (M.S., W.-J.L., C.J., S.F., C.B., S.R.S.), Medicine (A.C.S., C.B.), Geriatrics (S.R.S.), and Developmental and Regenerative Biology (K.A.K.), Friedman Brain Institute (S.R.S.), and Graduate School of Biomedical Sciences (M.S., C.J.), Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574; and Department of Integrative Biology and Physiology (C.E., M.R., A.G., A.B.), University of Minnesota, Minneapolis, Minnesota 55455-0001.

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 VGF(1-615) (hVGF) and mouse VGF(1-617) (mVGF), and to elucidate the function of the VGF C-terminal region in the regulation of energy balance and susceptibility to obesity, we generated humanized VGF knockin mouse models expressing full-length hVGF or a C-terminally deleted human VGF(1-524) (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 that VGF C-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 receptor binding affinity, likely alter the metabolic phenotype of hVGF compared with mVGF mice, and in hSNP mice in which several C-terminal VGF peptides are ablated, result in significantly increased activity- and nonactivity-related EE.

PMID:
25675362
PMCID:
PMC4398760
DOI:
10.1210/en.2014-1826
[Indexed for MEDLINE]
Free PMC Article

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