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

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.

• Authors: Eric Dale Buras, Lina Yang, Pradip Saha, Jongoh Kim, Pooja Mehta, Yisheng Yang, Susan Hilsenbeck, Hideto Kojima, Wenhao Chen, C Wayne Smith, Lawrence Chan
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 8 Pg. 3537-48 (Aug 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 25953849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Hypoglycemic Agents
• Tumor Necrosis Factor-alpha
• Proinsulin

Topics

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