VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity

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 Ay/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 addi...