Inflammation: The JNK diet

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JUN N-terminal kinase 1 (JNK1) promotes obesity-induced insulin resistance by regulating lipid accumulation in hematopoetic cells and promoting obesity-associated inflammation in non-hematopoetic cells.

In this study, Karin and colleagues unveil two new mechanisms of action for JUN N-terminal kinase 1 (JNK1) in promoting obesity-induced insulin resistance. They show that JNK1 expression in non-haematopoietic cells indirectly promotes insulin resistance by regulating lipid accumulation (a process known as adiposity), whereas JNK1 expression in haematopoietic cells promotes insulin resistance by promoting obesity-associated inflammation and the production of cytokines or other factors that directly induce insulin resistance.

Chronic low-grade inflammation that leads to the activation of protein kinases, such as JNK1, has an important role in the pathogenesis of obesity-induced insulin resistance. Indeed, previous studies have shown that JNK1 is chronically activated in obese tissues, inhibition of JNK1 protects against insulin resistance and JNK1 activation is required for adiposity. JNK1 directly inhibits insulin-receptor signalling in insulin target cells, but it is not known if the expression of JNK1 in macrophages or other myeloid cells contributes to high-fat diet (HFD)-induced insulin resistance and adiposity.

To investigate this possibility the authors generated chimeric mice that lacked JNK1 expression only in non-haematopoietic cells, which includes all insulin target cells, or only in haematopoietic cells, including myeloid cells. Jnk1^-/- mice are largely resistant to HFD-induced obesity, and with the use of the chimeric mice the authors found that this resistance was due to a loss of JNK1 expression in the non-haematopoietic-cell compartment. JNK1 deficiency in these cells resulted in an increase in energy expenditure and improved insulin sensitivity, owing in part to reduced adiposity. Therefore, in addition to restoring insulin signalling in insulin target cells, deletion of JNK1 in non-haematopoietic cells indirectly protects against HFD-induced insulin resistance by decreasing adiposity and thereby maintaining a leaner body mass.

Loss of JNK1 in haematopoietic cells did not protect mice from HFD-induced obesity but these mice showed improved insulin sensitivity. Interestingly, the loss of JNK1 in these cells resulted in reduced obesity-induced inflammation and a decrease in the expression of the pro-inflammatory cytokines interleukin-6 (IL-6), IL-12p40, tumour-necrosis factor (TNF), macrophage migration-inhibitory factor and CC-chemokine ligand 2 in the liver and adipose tissue. Furthermore, the number of macrophages in the adipose tissue was reduced in the absence of JNK1, even though there was no difference in their chemotatic activity or in the number of macrophages in the peripheral blood of these mice compared with controls.

Direct stimulation of wild-type macrophages or Kupffer cells with the saturated free fatty acid palmitate induced sustained JNK1 activation and Tnf and Il6 gene expression. In addition, palmitate-treated wild-type macrophages produced factors that directly induced insulin resistance in insulin target cells. Therefore, obesity-mediated activation of JNK1 in haematopoietic cells, such as macrophages and Kupffer cells, promotes chronic low-grade inflammation and the production of factors that directly induce insulin resistance in insulin target cells. These observations suggest that specific inhibition of JNK1 in haematopoietic cells could be an effective way to treat insulin resistance.

Olive Leavy

References

Solinas, G. et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. 6, 386–397 (2007) | Article | PubMed |