title: Germline ablation of VGF increases lipolysis in white adipose tissue.
abstract: Targeted deletion of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically induced obesity and diabetes. We hypothesized that increased sympathetic nervous system activity in Vgf-/Vgf- knockout mice is responsible for increased energy expenditure and decreased fat storage and that increased β-adrenergic receptor stimulation induces lipolysis in white adipose tissue (WAT) of Vgf-/Vgf- mice. We found that fat mass was markedly reduced in Vgf-/Vgf- mice. Within knockout WAT, phosphorylation of protein kinase A substrate increased in males and females, phosphorylation of hormone-sensitive lipase (HSL) (ser563) increased in females, and levels of adipose triglyceride lipase, comparative gene identification-58, and phospho-perilipin were higher in male Vgf-/Vgf- WAT compared with wild-type, consistent with increased lipolysis. The phosphorylation of AMP-activated protein kinase (AMPK) (Thr172) and levels of the AMPK kinase, transforming growth factor β-activated kinase 1, were decreased. This was associated with a decrease in HSL ser565 phosphorylation, the site phosphorylated by AMPK, in both male and female Vgf-/Vgf- WAT. No significant differences in phosphorylation of CREB or the p42/44 MAPK were noted. Despite this evidence supporting increased cAMP signaling and lipolysis, lipogenesis as assessed by fatty acid synthase protein expression and phosphorylated acetyl-CoA carboxylase was not decreased. Our data suggest that the VGF precursor or selected VGF-derived peptides dampen sympathetic outflow pathway activity to WAT to regulate fat storage and lipolysis.
authors.affiliation: Departments of Neuroscience Medicine Geriatrics, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Fargali
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.forename: Masato
authors.initials: M
authors.lastname: Sadahiro
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Salton
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D008066:Lipolysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D005230:Fatty Acids, Nonesterified; D009414:Nerve Growth Factors; D009479:Neuropeptides; C512697:Vgf protein, mouse