期刊
FASEB JOURNAL
卷 29, 期 8, 页码 3537-3548出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.15-271452
关键词
inflammation; obesity; diabetes; glucose
资金
- U.S. National Institutes of Health (NIH) [National Heart, Lung and Blood Institute (NHLBI)] [R01-HL51586]
- Diabetes Research Center [P30-DK079638]
- Core Laboratories at Baylor College of Medicine
- Betty Rutherford Chair in Diabetes Research at Baylor St. Luke's Medical Center (Houston, TX, USA)
- Frank and Cindy Liu Family Foundation
- Cunningham (Chris, Casey and Jennifer) Family Foundation
- T.T. & W.F. Chao Global Foundation
- American Diabetes Association [1-14-MN-01]
- NIH NHLBI training Grant [T32-HL66991]
- Medical Scientist Training Program at Baylor College of Medicine
- U.S. National Institutes of Health (NIH) (National Institute of Diabetes and Digestive and Kidney Diseases) [DK105527]
Adipose tissue macrophages (ATMs) play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet (HFD)-induced obesity has been shown to lead to ATM accumulation in rodents; however, the impact of hyperglycemia on ATMdynamics in HFD-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (BM)-derived cells (PI-BMDCs) in rodents. We fed a 60% HFD to C57BL6/J mice to produce an obese type 2 diabetes model. Absent in chow-fed animals, PI-BMDCs account for 60% of the ATMs in the type 2 diabetic mice. The PI-ATM subset expresses TNF-alpha and other inflammatory markers, and is highly enriched within crownlike structures (CLSs). We found that amelioration of hyperglycemia by different hypoglycemic agents forestalled PI-producing ATM accumulation and adipose inflammation in these animals. We developed a diphtheria toxin receptor-based strategy to selectively ablate PI-BMDCs among ATMs. Application of the maneuver in HFD-fed type 2 diabetic mice was found to lead to near total disappearance of complex CLSs and reversal of insulin resistance and hepatosteatosis in these animals. In sum, we have identified a novel ATM subset in type 2 diabetic rodents that underlies systemic insulin resistance.-Buras, E. D., Yang, L., Saha, P., Kim, J., Mehta, P., Yang, Y., Hilsenbeck, S., Kojima, H., Chen, W., Smith, C. W., Chan, L. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.
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