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

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Metabolism: clinical and experimental (Impact Factor: 3.89). 05/2011; 60(11):1610-9. DOI: 10.1016/j.metabol.2011.04.004
Source: PubMed


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.

Download full-text


Available from: Leonidas G Koniaris, Feb 25, 2015
13 Reads
  • Source
    • "Each mouse was weighed before fracture and again at sacrifice. Glucose tolerance testing (GTT) was performed on representative lean (n = 5) and HFD-fed (n = 5) mice preoperatively [24], [25]. Briefly, mice were fasted for 6 hours, anesthetized with isoflurane (5%) and tail vein blood was sampled using a commercially available glucometer (One Touch Ultra; Lifescan, Inc., Milpitas, CA, USA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Impaired healing and non-union of skeletal fractures is a major public health problem, with morbidity exacerbated in patients with diabetes mellitus (DM). DM is prevalent worldwide and affects approximately 25.8 million US adults, with >90% having obesity-related type 2 DM (T2DM). While fracture healing in type 1 DM (T1DM) has been studied using animal models, an investigation into delayed healing in an animal model of T2DM has not yet been performed. Methods Male C57BL/6J mice at 5 weeks of age were placed on either a control lean diet or an experimental high-fat diet (HFD) for 12 weeks. A mid-diaphyseal open tibia fracture was induced at 17 weeks of age and a spinal needle was used for intra-medullary fixation. Mice were sacrificed at days 7, 10, 14, 21, 28, and 35 for micro-computed tomography (μCT), histology-based histomorphometry and molecular analyses, and biomechanical testing. Results HFD-fed mice displayed increased body weight and impaired glucose tolerance, both characteristic of T2DM. Compared to control mice, HFD-fed mice with tibia fractures showed significantly (p<0.001) decreased woven bone at day 28 by histomorphometry and significantly (p<0.01) decreased callus bone volume at day 21 by μCT. Interestingly, fracture calluses contained markedly increased adiposity in HFD-fed mice at days 21, 28, and 35. HFD-fed mice also showed increased PPARγ immunohistochemical staining at day 14. Finally, calluses from HFD-fed mice at day 35 showed significantly (p<0.01) reduced torsional rigidity compared to controls. Discussion Our murine model of T2DM demonstrated delayed fracture healing and weakened biomechanical properties, and was distinctly characterized by increased callus adiposity. This suggests altered mesenchymal stem cell fate determination with a shift to the adipocyte lineage at the expense of the osteoblast lineage. The up-regulation of PPARγ in fracture calluses of HFD-fed mice is likely involved in the proposed fate switching.
    PLoS ONE 06/2014; 9(6):e99656. DOI:10.1371/journal.pone.0099656 · 3.23 Impact Factor
  • Source
    • "Clementi et al. [5] reported that lack of IL-6 enhanced pyruvate tolerance and attenuated hepatic inflammation without making a significant difference in insulin signaling. "
    Metabolism: clinical and experimental 09/2012; 61(12). DOI:10.1016/j.metabol.2012.09.001 · 3.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.
    The Journal of clinical investigation 12/2012; 123(1). DOI:10.1172/JCI64941 · 13.22 Impact Factor
Show more