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MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet
Vidya Gadang1, Rohit Kohli, Andriy Myronovych
1Department of Pathology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio;
Summary
Mixed-lineage kinase 3 (MLK3) deficiency reduces body fat and improves insulin resistance in mice fed a high-fat diet. MLK3 promotes saturated fatty acid-induced inflammation and metabolic dysfunction.
Area of Science:
- Molecular Biology
- Immunology
- Metabolic Disease
Background:
- Saturated fatty acids trigger the c-Jun NH₂-terminal kinase (JNK) pathway, leading to chronic inflammation and insulin resistance.
- Mixed-lineage kinase 3 (MLK3), a MAP3K, mediates JNK activation by saturated fatty acids in vitro, but its in vivo role is unclear.
Purpose of the Study:
- To investigate the role of MLK3 in diet-induced JNK activation and metabolic dysfunction in vivo.
- To examine the effects of MLK3 deficiency on obesity, inflammation, and insulin resistance.
Main Methods:
- Utilized MLK3-deficient (MLK3-KO) mice fed a high-fat diet for 16 weeks.
- Assessed body fat, energy expenditure, food consumption, and physical activity.
- Analyzed JNK activation, macrophage polarization, cytokine expression, and insulin sensitivity in vitro and in vivo.
Main Results:
- MLK3-KO mice exhibited reduced body fat and increased energy expenditure compared to wild-type (WT) mice.
- MLK3 deficiency attenuated palmitate-induced JNK activation and M1 macrophage polarization.
- Loss of MLK3 improved insulin resistance and decreased hepatic steatosis in diet-induced obesity.
Conclusions:
- MLK3 is a key mediator of saturated fatty acid-induced JNK activation in vivo.
- MLK3 promotes diet-induced metabolic dysfunction, including obesity, inflammation, and insulin resistance.
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