| 1. |
- Andersson, Christian X, 1973, et al.
(författare)
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Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes
- 2007
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Ingår i: J Biol Chem. - 0021-9258. ; 282:13, s. 9430-5
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.
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| 2. |
- Franckhauser, S., et al.
(författare)
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Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:7, s. 1306-16
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: IL-6 is released by the adipose tissue and increased circulating levels in obesity are associated with hyperinsulinaemia and insulin resistance. Short-term experiments suggest that increased IL-6 release by the skeletal muscle following exercise may improve insulin sensitivity. METHODS: In order to examine the effect of chronically elevated IL-6 levels, we overexpressed Il6 in skeletal muscle in mice using an electro-transfer procedure. RESULTS: Circulating IL-6 levels were increased and the animals rapidly lost both weight and body fat, but food intake was unchanged, which is consistent with the finding that IL-6 increased energy expenditure. Insulin levels were inappropriately elevated and combined with hypoglycaemia in spite of reduced 2-deoxy-D: -glucose uptake by skeletal muscle. Insulin-stimulated glucose uptake by skeletal muscles ex vivo was reduced, probably due to the decreased amounts of glucose transporter (GLUT)-4. Beta cell insulin content was increased, while apparent beta cell mass was unchanged. Circulating serum amyloid A cluster levels were increased tenfold due to a pronounced proinflammatory state in the liver with infiltration of inflammatory cells. However, no liver steatosis was found, which may be accounted for by concomitant AMP kinase activation. CONCLUSIONS/INTERPRETATION: Chronically elevated IL-6 levels lead to inappropriate hyperinsulinaemia, reduced body weight, impaired insulin-stimulated glucose uptake by the skeletal muscles and marked inflammation in the liver. Thus, the pleiotrophic effects of chronically elevated IL-6 levels preclude any obvious usefulness in treating obesity or its associated metabolic complications in man, despite the fact that weight reduction may be expected.
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| 3. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 48:1, s. 96-104
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined whether short-term 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, PPARgamma co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. METHODS: Ten non-diabetic 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 PPARgamma co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-alpha 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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| 4. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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The effect of PPARgamma ligands on the adipose tissue in insulin resistance
- 2005
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Ingår i: Prostaglandins Leukot Essent Fatty Acids. - : Elsevier BV. - 0952-3278. ; 73:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue.
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| 5. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Visfatin is an adipokine, but it is not regulated by thiazolidinediones
- 2006
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Ingår i: J Clin Endocrinol Metab. - : The Endocrine Society. - 0021-972X. ; 91:3, s. 1181-4
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Visfatin was recently reported to be expressed in human adipose tissue and to exert insulin-mimicking effects. OBJECTIVE: The objective of this study was to examine whether visfatin is a true adipokine and is expressed in isolated fat cells. We also examined whether visfatin is regulated by thiazolidinediones and, thus, can contribute to the ability of these agents to improve insulin sensitivity. DESIGN: This was an open-labeled drug therapy trial. SETTING: This study was performed at a university hospital. PATIENTS: Seven newly diagnosed and previously untreated type 2 diabetic patients and six healthy individuals with reduced insulin sensitivity participated in the study. INTERVENTION: Pioglitazone therapy (30-45 mg/d) was given for 3-4 wk. MAIN OUTCOME MEASURES: Serum and adipose tissue mRNA levels of visfatin and adiponectin were the main outcome measures. RESULTS: Visfatin mRNA is expressed in both adipose tissue and isolated adipocytes. Treatment with thiazolidinediones for 3-4 wk did not alter the gene expression or circulating levels of visfatin in either nondiabetic or the diabetic individuals, whereas adiponectin increased significantly. CONCLUSION: The present study shows that visfatin is a true adipokine, but it is not regulated by TZD and, thus, is unlikely to contribute to the insulin-sensitizing actions of these drugs.
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| 6. |
- Rotter Sopasakis, Victoria, 1972, et al.
(författare)
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Cytokine release from adipose tissue of nonobese individuals
- 2005
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Ingår i: Int J Obes (Lond). - : Springer Science and Business Media LLC. - 0307-0565. ; 29:9, s. 1144-7
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Tidskriftsartikel (refereegranskat)abstract
- Explants of human adipose tissue from nonobese subjects were cultured for 24 h with or without the presence of 20 ng/ml TNFalpha. Gene expression and/or medium concentrations of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1 RA), TNFalpha, IL-6, IL-8, resistin, PAI-1 and leptin were analysed. TNFalpha increased the mRNA levels of TNFalpha itself as well as IL-6, IL-8, IL-1beta and PAI-1, but not leptin. The medium concentrations of IL-1 RA, IL-6 and IL-8 were markedly increased by TNFalpha while no measurable release of TNFalpha, resistin or IL-1beta to the medium was found. Thus, human adipose tissue from nonobese individuals releases substantial amounts of IL-6, IL-8 and IL-1 RA and the gene expression of these cytokines, like that of IL-1beta and PAI-1, is regulated by TNFalpha. However, since neither TNFalpha, resistin or IL-1beta was found in the culture medium, such a regulatory effect by TNFalpha on adipose tissue in vivo is likely to be mediated through a paracrine mechanism where invaded inflammatory cells may play a critical role.
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