Abstract 414: Key Role of STAT4 Deficiency in the Hematopoietic Compartment on Insulin Resistance and Adipose Tissue Inflammation
Adipose tissue inflammation is a hallmark of obesity and contributes to insulin resistance (IR). Recent data from our lab showed that STAT4 global deficiency reduces inflammation and improves insulin sensitivity in obese mice. STAT4 is expressed in adipocytes and cells of hematopoietic lineage. The objective of this study was to determine the contribution of selective STAT4 deficiency in adipocyte vs hematopoietic cells to IR and adipose tissue inflammation. For this purpose we sub-lethally irradiated Stat-4-/-C57Bl6 mice and reconstituted them with bone marrow cells (BMC) from Stat-4+/+C57Bl6 congenic donors to restore STAT4 expression in BM- derived cells (STAT4-/- recipients). These mice were compared to irradiated C57Bl6 wild-type mice reconstituted with Stat-4-/-C57Bl6 BMCs to produce STAT4 deletion selectively in BM-derived cells (STAT4+/+ recipients). Mice received a HFD (60%kcal fat) for 12 weeks (n=7 mice/group). Body weights, plasma cholesterol, triglycerides and free fatty acids were not different between the STAT4+/+ and STAT4-/- recipients. However the STAT4-/- recipients had significantly increased fasted plasma glucose. Congruent with this data the IP-ITT and GTT showed significantly higher area under the curve for the STAT4-/- recipients indicating increased glucose intolerance and insulin resistance compared to STAT4+/+ recipients. Adipose tissue immune cell composition was determined by flow cytometry. The total number of CD45+ lymphocytes was significantly higher in the STAT4-/- recipients compared to STAT4+/+ recipients. Also, the numbers of CD3+CD4+ and CD3+CD8+ cells were significantly higher in the STAT4-/- recipient group. Adipocyte size was significantly higher and the number of crown-like structures was significantly increased in the STAT4 -/- recipients indicating adipocyte hypertrophy and increased macrophage infiltration. Following in vivo insulin stimulation, activation of IR and IRS-1 was increased in liver and muscle in the STAT4+/+ recipient group suggesting improved insulin signaling in the mice that received STAT4-/- BMCs. These studies provide clear evidence for the importance of STAT4 in hematopoietic cells in regulating IR and adipose tissue inflammation in obesity.
Author Disclosures: A.D. Dobrian: None. K. Ma: None. L.M. Glenn: None. M.A. Hatcher: None. B.A. Haynes: None. E.J. Lehrer: None. J.L. Nalder: None.
- © 2015 by American Heart Association, Inc.