title: Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice.
abstract: Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Foglesong
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Slater
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Jason
authors.initials: J
authors.lastname: Siu
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Vedat
authors.initials: V
authors.lastname: Yildiz
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Stephen R J
authors.initials: SR
authors.lastname: Salton
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; The Comprehensive Cancer Center (G.D.F., W.H., X.L., A.M.S., J.S., L.C.), The Ohio State University, Columbus, Ohio; and The Center for Biostatistics (V.Y.), The Ohio State University, Columbus, Ohio 43210; and Department of Neuroscience (S.R.J.S.), Icahn School of Medicine at Mount Sinai, New York, New York 10461.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D004777:Environment; D005508:Food Deprivation; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000187:drug effects / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D044101:Receptors, Melanocortin / Q000819:agonists; D012931:Social Environment; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D020738:Leptin; D009414:Nerve Growth Factors; D009479:Neuropeptides; D044101:Receptors, Melanocortin; C512697:Vgf protein, mouse