Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone

Lagathu, Claire; Bastard, Jean‐Philippe; Auclair, Martine; Maachi, Mustapha; Capeau, Jacqueline; Caron, Michel

doi:10.1016/j.bbrc.2003.10.013

Cited by 314 publications

(240 citation statements)

References 35 publications

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“…It is a proinflammatory cytokine in most cells, but it may also be anti-inflammatory in some cells and antagonise the effect of TNF-alpha [38]. IL-6 is proinflammatory in both the liver and adipose cells [12][13][14]39] and has repeatedly been shown to induce insulin resistance in both cells [6,[11][12][13][14]. This effect is, in part, due to the induction of suppressor of cytokine signalling 3 (SOCS-3), which binds to and impairs activation of the insulin receptor and IRS-1 in response to insulin [40,41].…”

Section: Discussionmentioning

confidence: 99%

“…Several experimental studies in adipose and liver cells [6,[11][12][13][14], as well as animal experiments where IL-6 has been chronically infused, have shown that IL-6 impairs insulin sensitivity and action in these cells and also induces insulin resistance in vivo [14,15]. However, insulin-like effects in skeletal muscle cells, associated with AMP kinase (AMPK) activation, have also been shown [16][17][18][19].…”

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confidence: 99%

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Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

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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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“…In contrast, IL6 has not been reported to alter ACAC expression or FASN expression in adipose tissue. However, IL6 has been demonstrated to reduce lipogenesis in 3T3-L1 adipocytes in association with a reduction in glucose transport (Lagathu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Methyl-β-cyclodextrin alters adipokine gene expression and glucose metabolism in swine adipose tissue

Ramsay

Blomberg²,

Caperna³

2013

Animal

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This study was designed to determine whether methyl-b-cyclodextrin (MCD) can substitute for albumin in incubation medium for neonatal swine adipose tissue explants, or whether MCD affects metabolism and cytokine expression. Subcutaneous adipose tissue explants (100 6 10 mg) were prepared from 21-day-old pigs. Explants were incubated in medium 199 supplemented with 25 mM HEPES, 1.0 nM insulin at 378C. The medium also contained bovine serum albumin (BSA) or MCD at 0%, 0.05%, 0.1%, 0.2% or 0.3%. Tissue explants were treated with these media for 1 h and then switched to the same basal incubation medium containing 0.05% BSA. Explants were removed from basal medium at 2 or 8 h of incubation, and real-time PCR was performed to assess expression of tumor necrosis a (TNF) and interleukin 6 (IL6), acetyl CoA carboxylase (ACAC) and fatty acid synthase (FASN). Alternatively, rates of 14 C-glucose oxidation and lipogenesis were monitored 6 insulin (100 nM), following MCD treatment. Incubation with BSA had minimal effects on gene expression or adipose tissue metabolism, only producing a doubling in TNF mRNA abundance ( P , 0.01). Treatment with MCD increased TNF mRNA abundance by eightfold ( P , 0.009), whereas IL6 gene expression increased a 100-fold ( P , 0.001) with a suppression in ACAC and FASN expression ( P , 0.01). This was paralleled by MCD inhibition of insulin-stimulated glucose oxidation and lipogenesis ( P , 0.001). Addition of a TNF antibody to the incubation medium alleviated this inhibition of insulin-stimulated glucose metabolism by ,30% ( P , 0.05).

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Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone

Cited by 314 publications

References 35 publications

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

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

Methyl-β-cyclodextrin alters adipokine gene expression and glucose metabolism in swine adipose tissue

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