Germline ablation of VGF increases lipolysis in white adipose tissue

    1. Stephen R Salton1,3
    1. Departments of
      3Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA
    1. (Correspondence should be addressed to S R Salton at Department of Neuroscience, Box 1065; Email: stephen.salton{at}


    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.

    • Received in final form 9 August 2012
    • Accepted 31 August 2012
    • Made available online as an Accepted Preprint 31 August 2012
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