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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.

SUBMITTER: Xu H

PROVIDER: S-EPMC296998 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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

Xu Haiyan H 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

The Journal of clinical investigation 20031201 12

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 ...[more]

PMID: 14679177

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Project description:AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE-RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE-/-) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE-/- mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE-/- mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE-/--HFD mice. RAGE-/- mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE-/- mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Dataset Information

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

Publications

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

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