Objective: To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. Research Methods and Procedures:Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation.

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.

SUMMARY The class IA phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110α catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110α in liver results in markedly blunted insulin signaling with decreased generation of PIP3 and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110β. As a result, mice with hepatic knockout of p110α display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110α in liver did not respond to metformin treatment. Together, these data indicate that the p110α isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.

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.

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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Highlights d Insulin-driven AKT phosphorylation, but not downstream signaling, is promoted by RAS d RAS action on AKT phosphorylation depends on PI3Ka d Insulin signaling in hepatocytes is driven by redundant PI3Ka and PI3Kb activities d Compound and not single-isoform inhibition of PI3Ka and PI3Kb causes hyperglycemia

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 antiinflammatory effect in adipose cells by impairing the IL-6 signal at several levels.Adipose tissue has long been regarded as important only for the storage and release of lipids. It is now known to be the largest endocrine organ in the body, secreting cytokines, hormones, and growth factors (commonly referred to as adipokines) that are important paracrine/endocrine regulators (1). Adipose tissue is also thought to play an important role in the low-grade chronic inflammation associated with obesity and insulin resistance (1). Obesity and enlarged fat cells alter the pattern of secreted adipokines, favoring release of the inflammatory cytokine, interleukin-6 (IL-6), 2 and reducing the antiinflammatory and insulin-sensitizing adipokine, adiponectin (1). IL-6 is an important activator of inflammation in both liver and adipose tissue. Interestingly, the IL-6 concentration in the interstitial fluid of the adipose tissue is ϳ50-fold higher than in circulation, which strongly supports its role as an important regulator in this tissue (2). In addition, the adipose tissue accounts for ϳ30% of the circulating IL-6 concentration (3).Several studies have shown that IL-6 impairs insulin signaling. For example, IL-6 has been shown to reduce expression of adiponectin in human adipose tissue and the insulin receptor substrate-1 (IRS-1) and glucose transporter 4 in 3T3-L1 cells (2, 4). IL-6 is also a well known inducer of suppressor of cytokine signaling (SOCS) proteins (5), and induction of SOCS1 and SOCS3 has been shown to inhibit insulin signaling by binding to the insulin receptor and IRS-1 (6 -8).Intracellular IL-6 signaling is initiated by the interaction of IL-6 with a plasma membrane receptor complex containing the signal transducer glycoprotein 130 (gp130). This results in the activation of Janus ki...