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FASEB J. 2015 Aug;29(8):3537-48. doi: 10.1096/fj.15-271452. Epub 2015 May 7.

Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

Author information

1
*Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
2
*Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan lchan@bcm.edu.

Abstract

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 ATM dynamics 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-α 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.

KEYWORDS:

diabetes; glucose; inflammation; obesity

PMID:
25953849
PMCID:
PMC4511209
DOI:
10.1096/fj.15-271452
[Indexed for MEDLINE]
Free PMC Article

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