Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
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.
Xu
Haiyan
H
Millennium Pharmaceuticals, Cambridge, Massachusetts, USA.
Barnes
Glenn T
GT
Yang
Qing
Q
Tan
Guo
G
Yang
Daseng
D
Chou
Chieh J
CJ
Sole
Jason
J
Nichols
Andrew
A
Ross
Jeffrey S
JS
Tartaglia
Louis A
LA
Chen
Hong
H
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015726:Giant Cells / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation; D007333:Insulin Resistance; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012313:RNA