Inhibition of vagally mediated immune-to-brain signaling by vanadyl sulfate speeds recovery from sickness

Daniel R. Johnson, Jason C. O'Connor, Robert Dantzer, Gregory G. Freund

Research output: Contribution to journalArticlepeer-review


To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1β and IL-6 but not TNF-α. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1β. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1β and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-IRA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by upregulating brain expression of IL-1β antagonists.

Original languageEnglish (US)
Pages (from-to)15184-15189
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
StatePublished - Oct 18 2005
Externally publishedYes


  • Neuroimmunity
  • Sickness behavior
  • Type 2 diabetes
  • Vanadium

ASJC Scopus subject areas

  • General


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