Inhibitor κB kinase is involved in the paracrine crosstalk between human fat and muscle cells

Abstract

OBJECTIVE: Adipose tissue is now considered as an endocrine and secretory organ, and some adipocyte factors are thought to play a major role in the induction of insulin resistance in skeletal muscle. Here we tested the hypothesis that the crosstalk between fat and muscle involves activation of inhibitor kB Kinase (IKK) in the myocytes. MEASUREMENTS: Adipocyte-conditioned culture medium was added to the muscle cells overnight, or human fat and muscle cells were kept in co-culture. Insulin signalling was subsequently analysed in the myocytes. Involvement of IKK was assessed using I229, a highly specific inhibitor of the IKK complex. RESULTS: Adipocyte-conditioned medium strongly inhibited insulin-induced serine phosphorylation of Akt in myocytes with a rapid parallel activation of the nuclear factor kB pathway in these cells. Conditioned medium lacking the perturbation of insulin signalling did not activate NF-kB. Insulin signalling to Akt was completely abrogated under co-culture conditions. The IKK inhibitor I229 did not affect protein expression of Akt, but fully restored insulin action in myocytes subjected to co-culture. CONCLUSION: These data show that the release of fat cell factors may rapidly induce insulin resistance in human skeletal muscle cells. This process appears to be mediated by an IKK/NF-kB dependent pathway. We suggest that inhibitors of IKK would be of use to counteract the negative crosstalk between fat and muscle.

Autocrine Action of Adiponectin on Human Fat Cells Prevents the Release of Insulin Resistance-Inducing Factors

“…Thus, the fold stimulation was reduced from 2.5 Ϯ 0.2 to 1.6 Ϯ 0.3 and from 3.7 Ϯ 0.9 to 1.9 Ϯ 0.4 (n ϭ 12) for GSK3␣ and GSK3␤ serine phosphorylation, respectively. Most importantly, adipocyte-conditioned medium, which mimicks the coculture condition (22), profoundly reduced insulin-stimulated GLUT4myc translocation in human skeletal muscle cells (Fig. 1B).…”

“…After 15 days, 60 -80% of seeded preadipocytes developed to differentiated adipose cells, as defined by cytoplasm completely filled with small or large lipid droplets. These cells were then used for the coculture experiments and for generation of adipocyte-conditioned medium, as recently described (22). Coculture.…”

From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

“…Mice that are hemizygous for IKK show lower fasting blood glucose and insulin levels and improved free fatty acid levels relative to littermate controls when placed on a high-fat diet (Yuan et al, 2001). Adipocytederived factors can act via IKK to induce insulin resistance in skeletal muscle (Dietze et al, 2004). Insulin-induced activation of Akt/PKB in myocytes was reduced after culture in adipocyte-conditioned medium and insulin sensitivity could be restored by inhibiting IKK.…”

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

“…Impaired insulin action in adipose tissue could represent an early step leading to the overall insulin resistance characteristic of aged and/or obese rats (Smith 2002). Moreover, recent in vitro studies have demonstrated that adipocyte-conditioned medium impairs insulin signaling in skeletal muscle cells (Dietze et al 2004) and hepatocytes (Wang et al 2006a). The data presented herein indicates that insulin resistance in oxidative muscles such as soleus and diaphragm develops later than in adipose tissue, suggesting that it could be a secondary effect caused by the prolonged alteration of adipose tissue insulin sensitivity.…”