MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet
| Autor: | Vidya Gadang, Anja Jaeschke, David Y. Hui, Andriy Myronovych, Diego Perez-Tilve, Rohit Kohli |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Physiology MAP Kinase Signaling System Endocrinology Diabetes and Metabolism Adipose Tissue White Energy metabolism Inflammation Bone Marrow Cells Biology Diet High-Fat Tissue Culture Techniques Mice Insulin resistance Non-alcoholic Fatty Liver Disease Physiology (medical) Internal medicine medicine Animals Obesity Cells Cultured Crosses Genetic Regulation of gene expression Mice Knockout MAP kinase kinase kinase Kinase Macrophages Fatty liver Articles medicine.disease MAP Kinase Kinase Kinases Fatty Liver Mice Inbred C57BL Endocrinology Biochemistry Gene Expression Regulation Liver Saturated fatty acid Cytokines medicine.symptom Insulin Resistance Energy Metabolism |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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