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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology*
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / methods
  • Hyperglycemia / drug therapy
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology*
  • Hypoglycemic Agents / pharmacology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Insulin Resistance / physiology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism
  • Obesity / physiopathology
  • Proinsulin / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Hypoglycemic Agents
  • Tumor Necrosis Factor-alpha
  • Proinsulin