STAT4 Deficiency Reduces Obesity-Induced Insulin Resistance and Adipose Tissue Inflammation
- Anca D. Dobrian1⇑,
- Elena V. Galkina2,
- Qian Ma1,
- Margaret Hatcher1,
- Sabai Myo Aye1,
- Mathew J. Butcher2,
- Kaiwen Ma3,
- Bronson A. Haynes1,
- Mark H. Kaplan4 and
- Jerry L. Nadler3
- 1Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia; the
- 2Department of Microbiology and Molecular and Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia; the
- 3Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia
- 4Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
- Corresponding author: Anca D. Dobrian, .
Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12–induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4−/−C57Bl6/J mice develop high-fat diet–induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4−/− mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8+ cells, and display increased alternative (M2) macrophage polarization. CD8+ cells, but not CD4+ cells, from STAT4−/− mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4−/− mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1275/-/DC1.
See accompanying commentary, p. 4002.
- Received September 25, 2012.
- Accepted August 6, 2013.
- © 2013 by the American Diabetes Association.
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