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Publication

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

Endocrinology | 2015

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.

Pubmed ID: 25675362 RIS Download

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Associated grants

Agency: NIMH NIH HHS, United States
Id: R21 MH083496
Agency: NIDDK NIH HHS, United States
Id: R01 DK071308
Agency: NIDDK NIH HHS, United States
Id: DK071308
Agency: NIDDK NIH HHS, United States
Id: DK074873
Agency: NIDDK NIH HHS, United States
Id: R03 DK082724
Agency: NIAAA NIH HHS, United States
Id: R01 AA023416
Agency: NIMH NIH HHS, United States
Id: R01 MH086499
Agency: NIDDK NIH HHS, United States
Id: DK083568
Agency: NIMH NIH HHS, United States
Id: MH086499
Agency: NIDDK NIH HHS, United States
Id: DK102496
Agency: NIDDK NIH HHS, United States
Id: R01 DK102496
Agency: NIDCR NIH HHS, United States
Id: R01 DE021996
Agency: NIDDK NIH HHS, United States
Id: DK082724
Agency: NIDDK NIH HHS, United States
Id: K08 DK074873
Agency: NIMH NIH HHS, United States
Id: R33 MH083496
Agency: NIDDK NIH HHS, United States
Id: 5T32DK07645
Agency: NIDDK NIH HHS, United States
Id: T32 DK007645
Agency: NIMH NIH HHS, United States
Id: T32 MH096678

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