Article

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

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AJP Endocrinology and Metabolism (Impact Factor: 4.09). 07/2013; 305(4). DOI: 10.1152/ajpendo.00197.2013
Source: PubMed

ABSTRACT 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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