MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet

AJP Endocrinology and Metabolism (Impact Factor: 3.79). 07/2013; 305(4). DOI: 10.1152/ajpendo.00197.2013
Source: PubMed


Saturated fatty acids activate the cJun NH2-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro, however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here we have used MLK3 deficient mice to examine the role of MLK3 in a saturated fat diet model of obesity. MLK3 KO mice fed a high fat diet enriched in medium chain saturated fatty acids for 16 weeks had decreased body fat compared to wild-type (WT) mice, due to increased energy expenditure, independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow derived macrophages in vitro, and obesity-induced JNK activation, macrophage infiltration into adipose tissue and expression of pro-inflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction.

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    • "Upon activation, JNK can phosphorylate serine 707 on STAT6, thereby deactivating it (Shirakawa et al., 2011). A study of Mφ polarization in obesity showed that mice lacking the JNK activator MLK3 were also deficient in M1 Mφ polarization (Gadang et al., 2013). The transcription factors PPARγ and PPARδ are activated by STAT6 and necessary for M2 polarization, and PPARδ -/-Mφ exhibit enhanced activation of JNK following treatment with adipocyte-conditioned medium, which contains the M2 cytokines IL-4 and IL-13 (Kang et al., 2008; Odegaard et al., 2007). "
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