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

Eric Dale Buras, Lina Yang, Pradip Saha, Jongoh Kim, Pooja Mehta, Yisheng Yang, Susan Hilsenbeck, Hideto Kojima, Wenhao Chen, C. Wayne Smith, Lawrence Chan

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3537-3548
Number of pages12
JournalFASEB Journal
Volume29
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • Diabetes
  • Glucose
  • Inflammation
  • Obesity

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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