Deletion of interleukin-6 improves pyruvate tolerance without altering hepatic insulin signaling in the leptin receptor-deficient mouse

Alicia H. Clementi, Allison M. Gaudy, Teresa A. Zimmers, Leonidas G. Koniaris, Robert A. Mooney

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Obesity is associated with increased circulating interleukin-6 (IL-6), which may contribute to hepatic insulin resistance by impairing insulin receptor signaling. This study was designed to assess the impact of the systemic absence of IL-6 on the development of insulin resistance and glucose intolerance in an obese mouse model. Systemic insulin, glucose, and pyruvate tolerance tests were performed in IL-6 knockout (IL6KO) mice that had been crossed with a genetically obese (leptin receptor-deficient mouse model [Lep db]) mouse model. Real-time reverse transcriptase polymerase chain reaction and Western blot analysis assessed cellular and molecular markers of insulin signaling, inflammation, and metabolism. Absence of IL-6 did not improve systemic glucose or insulin tolerance, but Lep db × IL6KO mice displayed a smaller blood glucose increase following a pyruvate challenge. These results suggest that loss of IL-6 in the context of obesity may locally reduce hepatic glucose production from a gluconeogenic precursor. Hepatic insulin-dependent insulin receptor autophosphorylation, Akt activation, and FoxO1 phosphorylation were similar between Lep db × IL6KO mice and Lep db controls. Basal gene expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase was reduced in male Lep db × IL6KO mice relative to Lep db controls; but gene expression of another regulatory enzyme, glucose-6-phosphatase, remained unaltered. Absence of IL-6 reduced gene expression of serum amyloid A and RelA in female Lep db mice, but did not alter hepatic triglyceride accumulation or lipogenic gene expression. Overall, our results suggest that IL-6 may be detrimental in obesity by contributing to elevated hepatic glucose output.

Original languageEnglish (US)
Pages (from-to)1610-1619
Number of pages10
JournalMetabolism: Clinical and Experimental
Volume60
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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