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Submitted on May 16, 2005
Accepted on August 22, 2005
Fishberg Department of Neuroscience and Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA; Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA; Current address: Wyeth Research, Cardiovascular and Metabolic Diseases, 200 Cambridgepark Row, Cambridge, MA 02140; Current address: Department of Physiology, University of Manitoba, 730 William Ave., Winnipeg, Manitoba R3E 3J7, Canada; Current address: Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591
* To whom correspondence should be addressed. E-mail: stephen.salton{at}mssm.edu.
Targeted deletion of the gene encoding the neuronal and endocrine secreted peptide precursor called VGF (non-acronymic) produces a lean, hypermetabolic, hyperactive mouse. Since 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 counter-regulatory 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, while MC4R-/MC4R- mice that are additionally deficient in VGF have improved insulin responsiveness at 7-8 weeks 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 following gold thioglucose (GTG) 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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