Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.

Hotamışlıgil, Gökhan S.; Arner, Peter; F, J; Atkinson, Richard L.; Spiegelman, Bruce M.

doi:10.1172/jci117936

Cited by 3,122 publications

(2,233 citation statements)

References 28 publications

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“…Pro-inflammatory markers, such as TNFα and IL-6 are overexpressed in adipose tissue in obesity [45,46], and in non-obese states of insulin resistance [47] IL-6 has also been shown to reduce the expression of aP2, adiponectin and PPARγ2 [16,48], markers of terminal adipocyte differentiation. There were no significant changes in the expression of either cytokine in the present study, which makes it unlikely that the increase in adiponectin and aP2 following thiazolidinedione treatment was due to an amelioration of local inflammation.…”

Section: Discussionmentioning

confidence: 99%

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

et al. 2004

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Aims/hypothesis: We examined whether shortterm treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPARγ co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. Methods: Ten nondiabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic-hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. Results: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPARγ co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-α increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. Conclusions/interpretation: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.

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Section: Discussionmentioning

confidence: 99%

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

et al. 2004

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“…Accumulating data then confirmed a specific up-regulation of genes encoding inflammatory factors and an over-production of many cytokines and chemokines in enlarged adipose tissue [5]. Furthermore, improvement in insulin sensitivity induced by weight loss was accompanied by a decrease in the expression of pro-inflammatory genes [28,29]. So adipose tissue inflammation was considered as a crucial event leading to metabolic syndrome, T2DM and atherosclerotic cardiovascular diseases.…”

Section: Adipose Tissuementioning

confidence: 93%

“…Hotamisligil and colleagues were the first to show an increased expression and production of TNFα in adipose tissue of obese individuals and its direct role in obesity-induced insulin resistance [28]. Accumulating data then confirmed a specific up-regulation of genes encoding inflammatory factors and an over-production of many cytokines and chemokines in enlarged adipose tissue [5].…”

Section: Adipose Tissuementioning

confidence: 99%

“…TNFα was the first pro-inflammatory cytokine implicated in pathogenesis of obesity-related insulin resistance and T2DM [28]. However, TNF-α antagonism has not demonstrated significant improvement on insulin sensitivity in patients with metabolic syndrome [76] or T2DM [77,78], but these pilot studies were probably underpowered as they were conducted on a short-time period in a limited number of patients.…”

Section: Anti-tnfαmentioning

confidence: 99%

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Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

1,511

972

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:It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes.

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“…Abnormal production of inflammatory cytokines, such as increased tumor necrosis factor (TNF)-a, in adipose tissue has been found in obese rodents and humans. 19,20 This dysregulation of cytokines could contribute, at least in part, to the insulin resistance caused by obesity. 21 In addition, it is also possible that insulin resistance per se might involve the development of obesity.…”

Section: Discussionmentioning

confidence: 99%

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

et al. 2005

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Objective: To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity. Subjects: In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) o25 kg/m 2 ), overweight (25pBMIo30 kg/m 2 ) and obese (BMIX30 kg/m 2 ). Methods: We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position À173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position À794, which both can affect promoter activity in different cells. Results: We detected four alleles: 5-, 6-, 7-and 8-CATT at position À794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7-or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P ¼ 0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P ¼ 0.030). In contrast, À173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((À173G/C)/(À794[CATT] 5-8 )) was associated with a decreased risk of obesity (P ¼ 0.025) and G/6-CATT with an increased risk of overweight (P ¼ 0.028). Conclusion: Promoter polymorphism in the MIF gene is linked with obesity.

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Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.

Cited by 3,122 publications

References 28 publications

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

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