title: MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet.
abstract: Saturated fatty acids activate the c-Jun 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 wk had decreased body fat compared with 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 proinflammatory 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.
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Vidya
authors.initials: V
authors.lastname: Gadang
authors.forename: Rohit
authors.initials: R
authors.lastname: Kohli
authors.forename: Andriy
authors.initials: A
authors.lastname: Myronovych
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Anja
authors.initials: A
authors.lastname: Jaeschke
mesh_terms: D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
keywords: inflammation; insulin resistance; mixed-lineage kinase 3; saturated fatty acids