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 1

Il-13–/– mice show increased body weight and blood glucose levels.

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Il-13–/– mice show increased body weight and blood glucose levels. (A...
(A) Body weight in normal chow–fed WT and Il-13–/– mice (C57BL/6 background; n = 7–10 per genotype). Inset: body composition at 7 months of age, determined by DEXA. (B) Reduced O2 consumption, but normal food intake and activity, as determined by metabolic cages in 4-month-old Il-13–/– mice. Average values from the light and dark cycles are shown. (C) Increased fasting glucose concentrations in Il-13–/– mice. (D) Il-13–/– mice exhibited dysregulated glucose metabolism. Blood glucose, serum insulin, and serum lactate levels of 7-month-old chow-fed WT and Il-13–/– mice were measured at 10 am (fasted state) or 10 pm (fed state). (E) TG, FFA, and cholesterol levels of WT and Il-13–/– mice were determined at 10 am and 10 pm. Data are mean ± SEM. *P < 0.05 vs. WT.