title: 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.affiliation: *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.
authors.forename: Eric Dale
authors.initials: ED
authors.lastname: Buras
authors.affiliation: *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.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.affiliation: *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.
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.affiliation: *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.
authors.forename: Jongoh
authors.initials: J
authors.lastname: Kim
authors.affiliation: *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.
authors.forename: Pooja
authors.initials: P
authors.lastname: Mehta
authors.affiliation: *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.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: *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.
authors.forename: Susan
authors.initials: S
authors.lastname: Hilsenbeck
authors.affiliation: *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.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: *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.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.affiliation: *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.
authors.forename: C Wayne
authors.initials: CW
authors.lastname: Smith
authors.affiliation: *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.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000379:methods; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D011384:Proinsulin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D014409:Tumor Necrosis Factor-alpha; D011384:Proinsulin
keywords: diabetes; glucose; inflammation; obesity