Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

•MLK2 and MLK3 are expressed by insulin-responsive tissues•MLK2 and MLK3 are required for HFD-induced JNK activation and insulin resistance•MLK2 and MLK3 contribute to HFD-induced obesity by regulating energy expenditure•The sympathoadrenal system contributes to metabolic regulation by MLK2/MLK3

SummarySaturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.

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