Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents

Somm, Emmanuel; Cettour-Rose, Philippe; Asensio, Cédric S.; Charollais, Anne; Klein, Marcella; Theander-Carrillo, Claudia; Juge-Aubry, Cristiana E.; Dayer, Jean‐Michel; Nicklin, Martin J.H.; Meda, Paolo; Rohner-Jeanrenaud, F.; Meier, Christoph A.

doi:10.1007/s00125-005-0046-x

Cited by 97 publications

(79 citation statements)

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“…38 In contrast to surface marker expression corresponding to anti-inflammatory M2-like cells, the large amounts of proinflammatory cytokines secreted by ATMs (Figure 5), in contrast to typical M2 macrophages, 39 support a role of ATMs in obesity-induced adipocyte dysfunction and metabolic disorders, although IL-Ra also may contribute to the onset of insulin resistance. 40 The high basal cytokine production of ATMs shown in this study does not necessarily imply that unstimulated ATMs secrete these large amounts of cytokines in situ, since ATMs could have been stimulated during their isolation and cultivation. However, our data reveal that ATMs have the capacity to produce large amounts of cytokines and that they are responsive to Toll-like receptor ligands and cytokines such as LPS and IFN-g ( Figure 5).…”

Section: Discussionmentioning

confidence: 70%

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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Objective: Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance, thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. Design and measurements: Stromal vascular cells (SVCs) and ATMs were isolated from human adipose tissues from different locations. We characterized ATMs phenotypically and functionally by flow cytometry, endocytosis assay and determination of secreted cytokines. For comparison, we used macrophages of the 'classical' (M1) and the 'alternative', anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Results: Like prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, haemoglobin scavenger receptor CD163 and integrin avb5. The number of cells expressing these molecules correlated significantly with the donors' body mass indices (BMIs). Notably, SVCs positive for the common monocyte/macrophage marker CD14 contained a considerable fraction of blood monocytes, the abundance of which did not correlate with the BMIs, pointing to the requirement of the surface markers identified here for the identification of ATMs. ATMs showed endocytic activities similar to M2 macrophages and accordingly secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNF-a, IL-6, IL-1, MCP-1 and MIP-1a was even higher in ATMs than in proinflammatory M1 macrophages. Conclusion: ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but they are competent to produce extensive amounts of inflammatory cytokines, which could considerably contribute to the development of insulin resistance.

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Section: Discussionmentioning

confidence: 70%

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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“…Another plausible explanation is that the ability of TLR4 deficiency to improve insulin resistance in adipose tissue and not muscle is regulated through PPARG , whose levels are up to 50-fold higher in adipose tissues than in skeletal muscles [47]. IL1RN may be involved in the described phenotype by virtue of its ability to reduce insulin sensitivity in muscle through a specific decrease in glucose uptake as recently described in rats [48]. Alternatively, it remains possible that plasma factor(s) dominantly affect insulin signalling in muscles by mechanisms that are independent of TLR4.…”

Section: Discussionmentioning

confidence: 86%

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

et al. 2007

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Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

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“…The interleukin-1 receptor antagonist (Il1rn) and Ssp1 were among the genes most dramatically repressed in WAT of ROR␣ sg/sg mice. IL1rn has been reported to be highly upregulated in WAT of obese humans and to regulate insulin sensitivity (21,45), while Il1rn-deficient mice exhibited decreased adiposity and increased energy expenditure (46). Ssp1 expression was found to be elevated in obesity, while neutralization of Ssp1 was shown to inhibit obesity-induced inflammation and insulin resistance (3,28).…”

Section: Discussionmentioning

confidence: 99%

“…7G). Increased expression of many of these genes, including Il1rn, Ssp1, and Cd44, has been linked to obesity-associated inflammation and insulin resistance (3,28,45,46).…”

Section: Comparison Of Gene Expression Profilesmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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AM. Transcriptional profiling reveals a role for ROR␣ in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol Genomics 43: 818 -828, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00206.2010.-Retinoid-related orphan receptor (ROR)␣4 is the major ROR␣ isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR␣-deficient staggerer mice (ROR␣ sg/sg ) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR␣ sg/sg mice. In contrast, overexpression of ROR␣ in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR␣ sg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR␣. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR␣ sg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR␣ sg/sg WAT. Moreover, ROR␣ sg/sg mice fed with an HFD were protected from the development of insulin resistance. ROR␣ sg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR␣ plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR␣ may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. staggerer mice; obesity; metabolic syndrome; macrophage; insulinresistance; diabetes; retinoid-related orphan receptors OBESITY IS A MAJOR GLOBAL health concern. In the United States alone, 30% of the general population is obese and an estimated 66% of all adults are overweight (40). Obesity is associated with an elevated risk of several pathologies, including Type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and airway disease (18,36). The molecular links between obesity and these diseases are beginning to be understood. It is now well recognized that obesity is associated with chronic low-grade inflammation and that inflammatory processes play an important role in obesity and related pathologies (18,44,53). Infiltration of macrophages and various T-lymphocytes in hypertrophic adipose tissues have been considered as important early events in the development of obesity-associated complications (14, 38, 57) and the release of proinflammatory cytokines by adipose tissue plays a key ...

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Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents

Cited by 97 publications

References 40 publications

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

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