Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
Haiyan Xu, Glenn T. Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J. Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia, Hong Chen
Haiyan Xu, Glenn T. Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J. Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia, Hong Chen
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Article Metabolism

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

Abstract

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

Authors

Haiyan Xu, Glenn T. Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J. Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia, Hong Chen

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Histological comparison between wild-type and ob/ob WAT and stromal-vasc...
Histological comparison between wild-type and ob/ob WAT and stromal-vascular cells. For each panel, the wild type at ×100 is seen at the left, ob/ob at ×100 in the middle, and ob/ob at ×400 at the right. (a) WAT morphological differences at 3 months (toluidine blue O on paraffin sections). Note the presence of nucleated stromal cells in the high magnification of the ob/ob type at the right. (b) WAT morphological differences at 5 months (toluidine blue O on paraffin sections). The stromal multinucleated cells have increased in the ob/ob type seen at the right, with early features of lipolysis in the ob/ob adipocytes manifested by multifocal cell shrinkage. (c) WAT at 3 months probed with F4/80 antisense RNA (in situ hybridization on fresh frozen sections). (d) WAT at 3 months immunostained with anti–F4/80 antibody (immunohistochemistry on paraffin sections, brown staining). (e) Primary stromal-vascular cells from 5-month-old mice, immunostained with anti–F4/80 antibody (red staining). (f) Primary stromal-vascular cells from 5-month-old mice stained with oil red O.