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 4

Dysregulation of hepatic gluconeogenic genes in Il-13–/– mice.

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Dysregulation of hepatic gluconeogenic genes in Il-13–/– mice. (A) The...
(A) The effect of feeding-induced suppression on gluconeogenic gene expression was blunted in Il-13–/– mice. Livers from 2-month-old chow-fed WT and Il-13–/– mice (C57BL/6 background; n = 6 per genotype) were collected at 10 am and 10 pm, and gene expression was examined by quantitative real-time PCR. (B) By 7 months of age, expression of the gluconeogenic pathway was further elevated in liver of chow-fed Il-13–/– mice (C57BL/6 background), which was normalized by rIL-13 injection (1 μg every other day, total 3 doses). Livers were collected at 10 pm. (C) Acute rIL-13 treatment rescued the glucose phenotype of Il-13–/– mice (cohort as in B). Blood glucose and lactate were measured at 10 pm. (D) Glucose production and gluconeogenic gene expression in primary hepatocytes derived from 4- to 5-month-old Il-13–/– mice. rIL-13 (10 ng/ml) was given to hepatocytes for 2 hours followed by a 4-hour glucose production assay in the presence of rIL-13. RNA was isolated 6 hours after rIL-13 treatment. Data are mean ± SEM. *P < 0.05.