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

Elizabeth Watson, Seung Hahm, Tooru M. Mizuno, Joan Windsor, Carla Montgomery, Philipp E. Scherer, Charles V. Mobbs, Stephen R J Salton

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Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)5151-5163
Number of pages13
JournalEndocrinology
Volume146
Issue number12
DOIs
StatePublished - Dec 2005

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Hyperinsulinism
Hyperglycemia
Obesity
Glucose
Insulin
Insulin Resistance
Aurothioglucose
Peptides
Liver Glycogen
Glucose Clamp Technique
Poisons
Adiponectin
Gene Deletion
Adiposity
High Fat Diet
Type 2 Diabetes Mellitus
Homeostasis
Carbohydrates
Diet
Neurons

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Watson, E., Hahm, S., Mizuno, T. M., Windsor, J., Montgomery, C., Scherer, P. E., ... Salton, S. R. J. (2005). VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. Endocrinology, 146(12), 5151-5163. https://doi.org/10.1210/en.2005-0588

VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. / Watson, Elizabeth; Hahm, Seung; Mizuno, Tooru M.; Windsor, Joan; Montgomery, Carla; Scherer, Philipp E.; Mobbs, Charles V.; Salton, Stephen R J.

In: Endocrinology, Vol. 146, No. 12, 12.2005, p. 5151-5163.

Research output: Contribution to journalArticle

Watson, E, Hahm, S, Mizuno, TM, Windsor, J, Montgomery, C, Scherer, PE, Mobbs, CV & Salton, SRJ 2005, 'VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity', Endocrinology, vol. 146, no. 12, pp. 5151-5163. https://doi.org/10.1210/en.2005-0588
Watson, Elizabeth ; Hahm, Seung ; Mizuno, Tooru M. ; Windsor, Joan ; Montgomery, Carla ; Scherer, Philipp E. ; Mobbs, Charles V. ; Salton, Stephen R J. / VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. In: Endocrinology. 2005 ; Vol. 146, No. 12. pp. 5151-5163.
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