title: Deletion of interleukin-6 improves pyruvate tolerance without altering hepatic insulin signaling in the leptin receptor-deficient mouse.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Alicia H
authors.initials: AH
authors.lastname: Clementi
authors.forename: Allison M
authors.initials: AM
authors.lastname: Gaudy
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Koniaris
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mooney
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019289:Pyruvic Acid / Q000378:metabolism*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D015850:Interleukin-6; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D019289:Pyruvic Acid