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VGF Ablation Blocks the Development of Hyperinsulinemia and Hyperglycemia in Several Mouse Models of Obesity

Fishberg Department of Neuroscience (E.W., S.H., T.M.M., J.W., C.M., C.V.M., S.R.J.S.) and Brookdale Department of Geriatrics and Adult Development (T.M.M., C.V.M., S.R.J.S.), Mount Sinai School of Medicine, New York, New York 10029; and Departments of Medicine and Cell Biology (P.E.S.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Stephen R. J. Salton, M.D., Ph.D., Fishberg Department of Neuroscience, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029. E-mail: stephen.salton{at}mssm.edu.

Targeted deletion of the gene encoding the neuronal and endocrine secreted peptide precursor called VGF (nonacronymic) produces a lean, hypermetabolic, hyperactive mouse. Because VGF mutant mice are resistant to specific forms of diet-, lesion-, and genetically induced obesity, we investigated the role that this polypeptide plays in glucose homeostasis. We report that VGF mutant mice have increased insulin sensitivity by hyperinsulinemic euglycemic clamp analysis, and by insulin and glucose tolerance testing. Blunted counterregulatory responses in VGF-deficient mice were likely influenced by their significantly lower liver glycogen levels. VGF deficiency lowered circulating glucose and insulin levels in several murine models of obesity that are also susceptible to adult onset diabetes mellitus, including A^y/a agouti, ob/ob, and MC4R^–/MC4R^– mice. Interestingly, ablation of Vgf in ob/ob mice decreased circulating glucose and insulin levels but did not affect adiposity, whereas MC4R^–/MC4R^– mice that are additionally deficient in VGF have improved insulin responsiveness at 7–8 wk of age, when lean MC4R^–/MC4R^– mice already have impaired insulin tolerance but are not yet obese. VGF mutant mice also resisted developing obesity and hyperglycemia in response to a high-fat/high-carbohydrate diet, and after gold thioglucose treatment, which is toxic to hypothalamic glucose-sensitive neurons. Lastly, circulating adiponectin, an adipose-synthesized protein the levels of which are correlated with improved insulin sensitivity, increased in VGF mutant compared with wild-type mice. Modulation of VGF levels and/or VGF signaling may consequently represent an alternative means to regulate circulating glucose levels and insulin sensitivity.

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