leukotriene-b4 and Insulin-Resistance

Topics: Adipose Tissue; Humans; Insulin Resistance; Leukotriene B4; Obesity

Galectin-3 and LTB

Topics: Animals; Anti-Inflammatory Agents; Galectin 3; Humans; Inflammation; Insulin; Insulin Resistance; Leukotriene B4; Obesity

NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear.. Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice.. LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

Topics: Animals; Diet, High-Fat; Endoribonucleases; Hepatocytes; Insulin Resistance; Leukotriene B4; Lipogenesis; Liver; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Protein Serine-Threonine Kinases; Receptors, Leukotriene B4

Leukotriene B4 (LTB4) production via the 5-lipoxygenase (5-LO) pathway contributes to the development of insulin resistance in adipose and hepatic tissues, but the role of LTB4 in skeletal muscle is relatively unknown. Here, the authors investigated the role of LTB4 in C2C12 myotubes in palmitic acid (PA)-induced ER stress, inflammation and insulin resistance. PA (750 μM) evoked lipotoxicity (ER stress, oxidative stress, inflammation and insulin resistance) in association with LTB4 production. 5-LO inhibition reduced all the lipotoxic effects induced by PA. On the other hand, PA did not induce cysteinyl leukotrienes (CysLTs), which themselves had no effect on ER stress and inflammation. The beneficial effects of 5-LO suppression from PA-induced lipotoxicity were related with AMPK activation. In ob/ob mice, once daily oral administration of zileuton (50, 100 mg/kg) for 5 weeks improved insulin resistance, increased AMPK phosphorylation, and reduced LTB4 and ER stress marker expression in skeletal muscle. These results show that 5-LO inhibition by either zileuton or 5-LO siRNA protects C2C12 myotubes from PA-induced lipotoxicity, at least partly via AMPK activation, and suggest that the in vivo insulin-sensitizing effects of zileuton are in part attributable to its direct action on skeletal muscle via LTB4 downregulation followed by AMPK activation.

Topics: AMP-Activated Protein Kinases; Animals; Arachidonate 5-Lipoxygenase; Cell Line; Endoplasmic Reticulum Stress; Hydroxyurea; Insulin Resistance; Leukotriene B4; Lipoxygenase Inhibitors; Mice; Muscle Fibers, Skeletal; Oxidative Stress; Palmitic Acid; Phosphorylation

Tissue inflammation is a key component of obesity-induced insulin resistance, with a variety of immune cell types accumulating in adipose tissue. Here, we have demonstrated increased numbers of B2 lymphocytes in obese adipose tissue and have shown that high-fat diet-induced (HFD-induced) insulin resistance is mitigated in B cell-deficient (Bnull) mice. Adoptive transfer of adipose tissue B2 cells (ATB2) from wild-type HFD donor mice into HFD Bnull recipients completely restored the effect of HFD to induce insulin resistance. Recruitment and activation of ATB2 cells was mediated by signaling through the chemokine leukotriene B4 (LTB4) and its receptor LTB4R1. Furthermore, the adverse effects of ATB2 cells on glucose homeostasis were partially dependent upon T cells and macrophages. These results demonstrate the importance of ATB2 cells in obesity-induced insulin resistance and suggest that inhibition of the LTB4/LTB4R1 axis might be a useful approach for developing insulin-sensitizing therapeutics.

Topics: Adipose Tissue; Animals; B-Lymphocyte Subsets; Dietary Fats; Insulin Resistance; Leukotriene B4; Macrophages; Mice; Mice, Knockout; Obesity; Receptors, Leukotriene B4; Signal Transduction; T-Lymphocytes

Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase-activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

Topics: 5-Lipoxygenase-Activating Proteins; Adipose Tissue; Adipose Tissue, White; Animals; Diet, High-Fat; Gene Expression; Hep G2 Cells; Humans; Insulin Resistance; Leukotriene B4; Lipoxins; Mice; Mice, Transgenic; Obesity; Thermogenesis

Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.

Topics: Animals; Blood Glucose; Diet, High-Fat; Fatty Liver; Hepatocytes; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leukotriene B4; Macrophages; Mice; Mice, Obese; Muscle Fibers, Skeletal; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leukotriene B4; Signal Transduction

The potent chemokine leukotriene B4 (LTB4) is increased in obesity, and is associated with insulin resistance. A recent article shows that inhibition of its receptor LTB4 receptor 1 (Ltb4r1) improves insulin sensitivity in muscle and liver via cytokine-independent mechanisms, and reduces proinflammatory immune cell infiltration in the adipose tissue.

Topics: Animals; Hepatocytes; Insulin Resistance; Leukotriene B4; Macrophages; Muscle Fibers, Skeletal; Obesity; Receptors, Leukotriene B4

Various inflammatory mediators related to obesity might be closely related to insulin resistance. Leukotrienes (LTs) are involved in inflammatory reactions. However, there are few reports regarding the role of LTs in adipocyte differentiation. Therefore, we investigated the role of leukotriene B4 (LTB4)-leukotriene receptor (BLT) signaling in mouse 3T3-L1 fibroblastic preadipocyte differentiation to mature adipocytes.. Mouse 3T3-L1 preadipocytes were treated with lipoxygenase (LOX) inhibitors, BLT antagonist, and small interfering RNA (siRNA) for BLT1 and BLT2 to block the LTB4-BLT signaling pathway, then the adipocyte differentiation such as lipid accumulation and the increase in triglyceride was evaluated.. Blockade of BLT signaling by treatment with a LOX inhibitor or a BLT antagonist suppressed preadipocyte differentiation into mature adipocytes. In addition, knockdown of BLT1 and BLT2 by siRNAs dramatically inhibited differentiation. These results indicate the LTB4-BLT signaling pathway may positively regulate preadipocyte differentiation and be a rate-limiting system to control adipocyte differentiation.. The LTB4-BLT signaling pathway provides a potent regulatory signal that accelerates the differentiation of mouse 3T3-L1 preadipocytes. Further investigations are necessary to confirm the exact role of LTB4 and BLTs signaling pathways in preadipocyte differentiation.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Differentiation; Insulin Resistance; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Mice; Obesity; Receptors, Leukotriene B4; RNA, Small Interfering; Signal Transduction

The work was designed to study levels of serum prostaglandin F1a (6-keto-PGF1a), thromboxane B2, and leukotriene B4 (LTB4)--stable products of cyclooxygenase and lipogenase-catalyzed reactions of arachidonic acid, in patients with metabolic syndrome (MS) differing in glucose homeostasis. It was shown that MS is associated with excess production of anti-inflammatory oxilipines (LTB4) regardless of the presence or absence of insulin resistance. LTB4 are known to influence inflammatory processes due to compensatory synthesis of vasodilating eicosanoids (6-keto-PGF1a) that antagonize vasoconctriction and inflammation. Combination of MS with insulin resistance in patients with elevated LTB4 and 6-keto-PGF1a levels is associated with enhanced synthesis of thromboxane A2 responsible for vasoconstriction, platelet formation, and development of endothelial dysfunction. The study suggests disturbed synthesis of eicosanoids in patients with MS and their important role in pathogenesis of this condition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Eicosanoids; Female; Humans; Insulin Resistance; Leukotriene B4; Male; Metabolic Syndrome; Middle Aged; Thromboxane B2; Young Adult