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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #329128

Research Project: Molecular, Cellular, and Regulatory Aspects of Nutrition During Development

Location: Children's Nutrition Research Center

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

Author
item Buras, Ed - Children's Nutrition Research Center (CNRC)
item Yang, L - Children's Nutrition Research Center (CNRC)
item Saha, P - Children's Nutrition Research Center (CNRC)
item Kim, J - Children's Nutrition Research Center (CNRC)
item Mehta, P - Children's Nutrition Research Center (CNRC)
item Yang, Y - Children's Nutrition Research Center (CNRC)
item Hilsenbeck, S - Children's Nutrition Research Center (CNRC)
item Kojima, H - Children's Nutrition Research Center (CNRC)
item Chen, W - Children's Nutrition Research Center (CNRC)
item Smith, Cw - Children's Nutrition Research Center (CNRC)
item Chan, L - Baylor College Of Medicine

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2015
Publication Date: 8/29/2015
Citation: Buras, E., Yang, L., Saha, P., Kim, J., Mehta, P., Yang, Y., Hilsenbeck, S., Kojima, H., Chen, W., Smith, C.W., Chan, L. 2015. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice. Federation of American Societies for Experimental Biology Conference. 29:3537-3548.

Interpretive Summary: Obesity and type II diabetes are diseases of global metabolic importance. This study in mice used a high fat diet to produce elevated blood sugar levels, insulin resistance and liver changes like those found in early diabetes. The mice became obese and their fat pads began to increase in a unique type of white blood cell that migrates into the tissue. Treating the mice to specifically remove this type of white blood cell was beneficial, preventing the diet-induced liver changes and insulin resistance. This work raises the question of whether this unique type of white blood cell occurs in humans with diet-induced type II diabetes as a possible target for future therapies.

Technical Abstract: Adipose tissue macrophages play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet-induced obesity has been shown to lead to adipose tissue macrophages accumulation in rodents;however, the impact of hyperglycemia on adipose tissue macrophages dynamics in high-fat diet-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin-producing proinflammatory bone marrow-derived cells in rodents. We fed a 60% high-fat diet to C57BL6/J mice to produce an obese type 2 diabetes model. Absent in chow-fed animals, proinsulin-producing proinflammatory bone marrow-derived cells account for 60% of the adipose tissue macrophages in the type 2 diabetic mice. The proinsulin-adipose tissue macrophages subset expresses TNF-a and other inflammatory markers, and is highly enriched within crownlike structures. We found that amelioration of hyperglycemia by different hypoglycemic agents forestalled proinsulin-producing adipose tissue macrophages accumulation and adipose inflammation in these animals. We developed a diphtheria toxin receptor-based strategy to selectively ablate proinsulin-producing proinflammatory bone marrow-derived cells in high-fat diet-fed type 2 diabetic mice was found to lead to near total disappearance of complex crownlike structures and reversal of insulin resistance and hepatosteatosis in these animals. In sum, we have identified a novel adipose tissue macrophages subset in type 2 diabetic rodents that underlies systemic insulin resistance.