Direct control of hepatic glucose production by interleukin-13 in mice
Kristopher J. Stanya, … , Andrew N.J. McKenzie, Chih-Hao Lee
Kristopher J. Stanya, … , Andrew N.J. McKenzie, Chih-Hao Lee
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):261-271. https://doi.org/10.1172/JCI64941.
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Research Article

Direct control of hepatic glucose production by interleukin-13 in mice

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.

Authors

Kristopher J. Stanya, David Jacobi, Sihao Liu, Prerna Bhargava, Lingling Dai, Matthew R. Gangl, Karen Inouye, Jillian L. Barlow, Yewei Ji, Joseph P. Mizgerd, Ling Qi, Hang Shi, Andrew N.J. McKenzie, Chih-Hao Lee

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Figure 6

IL-13 suppresses gluconeogenic gene expression through STAT3.

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IL-13 suppresses gluconeogenic gene expression through STAT3. (A) Immuno...
(A) Immunoblotting showing reduced p-STAT3 levels in Il-13–/– liver. Liver samples were collected at 10 pm (2 representative mice per group; cohort as in Figure 4B). (B) Immunoblotting showed that IL-13 induced STAT3/STAT6 phosphorylation in primary hepatocytes from WT, liver-specific Stat3–/–, and Stat6–/– mice. (C) IL-13 suppressed glucose production in hepatocytes in a STAT3-dependent manner. (D) IL-13 decreased expression of gluconeogenic genes through STAT3. Samples were collected 6 hours after rIL-13 treatment for gene expression analyses by quantitative real-time PCR. (E) Suppression of PEPCK promoter activity by IL-13 was mediated by STAT3. Stat3–/– hepatocytes were transfected with a luciferase reporter driven by PEPCK promoter, STAT3 expression vector, and/or rIL-13. RLU, relative luciferase unit. (F) ChIP in WT and Stat3–/– hepatocytes showed STAT3 occupancy on Pepck and G6p promoters induced by IL-13. ND, not detected. (G) IL-13Rα1 was required for IL-13–dependent inhibition of glucose production. Hepatocytes were isolated from WT mice and transfected with siRNAs targeting either Il-13rα1 (siIL-13Rα1) or Stat3 (siSTAT3). siControl, control siRNA. Immunoblotting of p-STAT3 and total STAT3 in hepatocytes transfected with control or IL-13Rα1 siRNA is also shown. Samples were run on the same gel but were noncontiguous (white lines). (H) IL-13Rα1 mediated IL-13–dependent inhibition on gluconeogenic gene expression, as assessed by quantitative real-time PCR. Glucose production and gene expression are presented as fold change relative to control. Data are mean ± SEM. *P < 0.05 vs. vehicle, or as indicated by brackets.