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.
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