Complex neural circuits and a large number of peptide hormones and neuropeptides control feeding and energy expenditure. The VGF (non-acronymic) gene encodes a highly conserved mammalian polypeptide that is differentially cleaved in a tissue-specific manner and secreted from endocrine, neuroendocrine and neuronal cells. We have shown that targeted deletion of VGF results in profound alterations in the regulation of feeding and energy balance; VGF mutant mice are lean, hyperactive, hypermetabolic and highly resistant to obesity and diabetes. Interestingly, a number of independent genetic linkage studies have consistently shown strong evidence of a subregion linked with obesity over the VGF locus on 7q22.1 but the causative gene has not been identified. Based on its consistent linkage in independent studies and strong biological candidacy, we hypothesize that VGF is an excellent candidate gene for human obesity and leanness, and propose to investigate this using combined clinical and basic science approaches. One of us (JAM) will perform genetic association studies using a high density panel of single nucleotide polymorphisms (SNPs) in the Quebec Family Study (QFS) patient cohort who represents well-characterized samples from 950 individuals and 223 families. Several nonsynonymous, protein-altering SNPs are already known and additional SNPs across the VGF locus will be developed and fully characterized as potential functional variants and/or biomarkers. These SNPs and haplotype blocks will then be validated in a second, independent cohort of 1,425 individuals. Concurrent biologic studies (SRJS) will investigate the function of select human VGF SNPs in mouse models using gene 'knockout' and 'knock-in' strategies, and in various in vitro cell culture models where VGF expression, processing, and regulated release can be quantified. Since targeted VGF deletion generates mice that are lean and resistant to diet-induced and some forms of genetically-induced obesity, tissues from these mice, including adipose and muscle, will be used to identify additional gene products by high-density gene expression array analysis. These physiologically linked, target-tissue genes may themselves play a functional role in obesity resistance or susceptibility, and thus become excellent candidates for future investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071308-02
Application #
7021385
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J2))
Program Officer
Sato, Sheryl M
Project Start
2005-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$331,034
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Stephens, Samuel B; Edwards, Robert J; Sadahiro, Masato et al. (2017) The Prohormone VGF Regulates ? Cell Function via Insulin Secretory Granule Biogenesis. Cell Rep 20:2480-2489
Jiang, Cheng; Lin, Wei-Jye; Sadahiro, Masato et al. (2017) Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight. Neuropeptides 64:75-83
Foglesong, Grant D; Huang, Wei; Liu, Xianglan et al. (2016) Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice. Endocrinology 157:983-96
Sadahiro, Masato; Erickson, Connor; Lin, Wei-Jye et al. (2015) Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: analysis of ""humanized"" knockin mice expressing full-length or truncated VGF. Endocrinology 156:1724-38
Fargali, Samira; Garcia, Angelo L; Sadahiro, Masato et al. (2014) The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. FASEB J 28:2120-33
Fargali, Samira; Sadahiro, Masato; Jiang, Cheng et al. (2012) Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis. J Mol Neurosci 48:654-9
Fargali, Samira; Scherer, Thomas; Shin, Andrew C et al. (2012) Germline ablation of VGF increases lipolysis in white adipose tissue. J Endocrinol 215:313-22
Watson, Elizabeth; Fargali, Samira; Okamoto, Haruka et al. (2009) Analysis of knockout mice suggests a role for VGF in the control of fat storage and energy expenditure. BMC Physiol 9:19
Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie et al. (2008) The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 28:9857-69
Sakurai, Takeshi; Gil, Orlando D; Whittard, John D et al. (2008) Interactions between the L1 cell adhesion molecule and ezrin support traction-force generation and can be regulated by tyrosine phosphorylation. J Neurosci Res 86:2602-14

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