title: 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.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Ave., Boston, Massachusetts 02115, USA.
authors.forename: Kristopher J
authors.initials: KJ
authors.lastname: Stanya
authors.forename: David
authors.initials: D
authors.lastname: Jacobi
authors.forename: Sihao
authors.initials: S
authors.lastname: Liu
authors.forename: Prerna
authors.initials: P
authors.lastname: Bhargava
authors.forename: Lingling
authors.initials: L
authors.lastname: Dai
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gangl
authors.forename: Karen
authors.initials: K
authors.lastname: Inouye
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Barlow
authors.forename: Yewei
authors.initials: Y
authors.lastname: Ji
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005943:Gluconeogenesis / Q000235:genetics / Q000276:immunology; D005947:Glucose / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D005947:Glucose