MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet
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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- "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). "
ABSTRACT: Macrophages, found in circulating blood as well as integrated into several tissues and organs throughout the body, represent an important first line of defense against disease and a necessary component of healthy tissue homeostasis. Additionally, macrophages that arise from the differentiation of monocytes recruited from the blood to inflamed tissues play a central role in regulating local inflammation. Studies of macrophage activation in the last decade or so have revealed that these cells adopt a staggering range of phenotypes that are finely tuned responses to a variety of different stimuli, and that the resulting subsets of activated macrophages play critical roles in both progression and resolution of disease. This review summarizes the current understanding of the contributions of differentially polarized macrophages to various infectious and inflammatory diseases and the ongoing effort to develop novel therapies that target this key aspect of macrophage biology.Moleculer Cells 03/2014; 37(4). DOI:10.14348/molcells.2014.2374 · 2.24 Impact Factor
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ABSTRACT: The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet-induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway.Genes & development 11/2013; 27(21):2345-55. DOI:10.1101/gad.223800.113 · 12.64 Impact Factor
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ABSTRACT: Monocytes/macrophages are heterogeneous and versatile cells could undergo their phenotype/function dynamic switch in response to the microenvironment signals. Two major macrophages subpopulations with different functions which represent extreme of a continuum in a universe of activation states, including classically activated/inflammatory (M1) and alternatively activated/regenerative (M2) macrophages, have long been recognized. Emerging evidence through genetic or pharmacologic approaches has now been made in defining the actual fate in vivo and in vitro underlying M1 or M2-like polarized activation under physiological and pathological conditions. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Here in this review, we shed new light on the contribution of several major signaling pathways and their modulators/targets involved in directing the macrophage plasticity and polarized function, assess the mechanisms of macrophage polarization by interacting endogenous cellular mechanisms and molecules associated with reciprocal skewing of macrophage polarization between the M1 and M2 state. The identification of mechanisms underlying functional polarization of macrophages into M1 or M2 cells might provide new insights into a basis for macrophage-centered diagnostic and therapeutic strategies for multiple diseases.Cellular Signalling 11/2013; 26(2). DOI:10.1016/j.cellsig.2013.11.004 · 4.47 Impact Factor