title: Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight.
abstract: Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice. Adult male and female mice, with conditional ablation of the Vgf gene in embryonic neurons had significantly reduced body weight, increased energy expenditure, and were resistant to diet-induced obesity. Conditional forebrain postnatal ablation of VGF in male mice, primarily in adult excitatory neurons, had no measurable effect on body weight nor on energy expenditure, but led to a modest increase in adiposity, partially overlapping the effect of AAV-Cre-mediated targeted ablation of VGF in the adult ventromedial hypothalamus and arcuate nucleus of floxed Vgf mice (Foglesong et al., 2016), and also consistent with results of icv delivery of the VGF-derived peptide TLQP-21 to adult mice, which resulted in increased energy expenditure and reduced adiposity (Bartolomucci et al., 2006). Because the lean, hypermetabolic phenotype of germline VGF knockout mice is to a great extent recapitulated in Syn-Cre+/-,Vgfflpflox/flpfloxmice, we conclude that the metabolic profile of germline VGF knockout mice is largely the result of VGF ablation in embryonic CNS neurons, rather than peripheral endocrine and/or neuroendocrine cells, and that in forebrain structures such as hypothalamus, VGF and/or VGF-derived peptides play uniquely different roles in the developing and adult nervous system.
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: cheng.jiang@icahn.mssm.edu.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: weijye.lin@mssm.edu.
authors.forename: Wei-Jye
authors.initials: WJ
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: masato.sadahiro@icahn.mssm.edu.
authors.forename: Masato
authors.initials: M
authors.lastname: Sadahiro
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: andrew.shin@mssm.edu.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: christoph.buettner@mssm.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: stephen.salton@mssm.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Salton
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D004032:Diet; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D009414:Nerve Growth Factors; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D009479:Neuropeptides; C512697:Vgf protein, mouse
keywords: Adipose; Brain-derived neurotrophic factor (BDNF); Chromogranin; Diet-induced obesity; Energy expenditure; Hypothalamus; Neuropeptide; Secretogranin; Synapsin-Cre; VGF (non-acronymic)