title: IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity.
abstract: Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor α (PPARα) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPARα-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.
authors.affiliation: Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Roberto R
authors.initials: RR
authors.lastname: Ricardo-Gonzalez
authors.forename: Alex
authors.initials: A
authors.lastname: Red Eagle
authors.forename: Justin I
authors.initials: JI
authors.lastname: Odegaard
authors.forename: Hani
authors.initials: H
authors.lastname: Jouihan
authors.forename: Christine R
authors.initials: CR
authors.lastname: Morel
authors.forename: Jose E
authors.initials: JE
authors.lastname: Heredia
authors.forename: Lata
authors.initials: L
authors.lastname: Mukundan
authors.forename: Davina
authors.initials: D
authors.lastname: Wu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Locksley
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D007333:Insulin Resistance / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D047493:PPAR alpha; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4