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Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
Haiyan Xu, … , Louis A. Tartaglia, Hong Chen
Haiyan Xu, … , Louis A. Tartaglia, Hong Chen
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1821-1830. https://doi.org/10.1172/JCI19451.
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Article Metabolism

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

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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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Figure 1

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(a) The transcriptional regulation of inflammation genes in the WAT of m...
(a) The transcriptional regulation of inflammation genes in the WAT of mice with genetic or diet-induced obesity/diabetes by quantitative RT-PCR (TaqMan). For comparison, the expression level of these genes in lean mice was arbitrarily set at 1; error bars represent ± SE. LF, low fat (10% fat); HF, high fat (60% fat). ob/ob and db/db mice and appropriate controls (n = 5 per group) were obtained from The Jackson Laboratory, fed a standard chow diet (Farmer’s Exchange), and sacrificed at 15 weeks of age. DIO mice (C57BL/6J; The Jackson Laboratory) were obtained at 4 weeks of age and placed on the designated diet of 60% kcal from fat (Research Diets Inc.) for 16 weeks (n = 10 per group). y axes show arbitrary units representing relative expression levels of mRNAs. (b) Confirmation of inflammation-gene regulation by Northern blot analysis. An independent set of animals from the same experiment was used.

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