Nunemaker, C. S. et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am. J. Physiol. Endocrinol. Metab. 295, E1065-E1075

Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
AJP Endocrinology and Metabolism (Impact Factor: 4.09). 10/2008; 295(5):E1065-75. DOI: 10.1152/ajpendo.90371.2008
Source: PubMed

ABSTRACT Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.

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    • "Mouse pancreatic islets were isolated following euthanization as described previously [9] [15]. "
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    ABSTRACT: Type 2 diabetes is associated with obesity, insulin resistance, and inflammation in adipose tissue. 12/15-Lipoxygenase (12/15-LO) generates proinflammatory lipid mediators, which induce inflammation in adipose tissue. Therefore we investigated the role of 12/15-LO activity in mouse white adipose tissue in promoting obesity-induced local and systemic inflammatory consequences. We generated a mouse model for fat-specific deletion of 12/15-LO, aP2-Cre; 12/15-LO(loxP/loxP), which we call ad-12/15-LO mice, and placed wild-type controls and ad-12/15-LO mice on a high-fat diet for 16 weeks and examined obesity-induced inflammation and insulin resistance. High-fat diet-fed ad-12/15-LO exhibited improved fasting glucose levels and glucose metabolism, and epididymal adipose tissue from these mice exhibited reduced inflammation and macrophage infiltration compared to wild-type mice. Furthermore, fat-specific deletion of 12/15-LO led to decreased peripheral pancreatic islet inflammation with enlarged pancreatic islets when mice were fed the high-fat diet compared to wild-type mice. These results suggest an interesting crosstalk between 12/15-LO expression in adipose tissue and inflammation in pancreatic islets. Therefore, deletion of 12/15-LO in adipose tissue can offer local and systemic protection from obesity-induced consequences, and blocking 12/15-LO activity in adipose tissue may be a novel therapeutic target in the treatment of type 2 diabetes.
    Mediators of Inflammation 12/2012; 2012:851798. DOI:10.1155/2012/851798 · 3.24 Impact Factor
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    • "Mice with a deletion in 12-LO were resistant to the induction of diabetes by low dose streptozotocin (Bleich et al., 1999) and the 12-LO knockout mice lacked cytokine-induced conversion of arachidonic acid to 12-HETE, implying that 12-HETE generation was cytotoxic to beta cells (Bleich et al., 1999). Elevated levels of 12-LO co-associate with defects in insulin secretion in diabetic Zucker fatty rats (Tokuyama et al., 1995) and 12-LO knockout mice are resistant to the inflammatory effects of obesity induced by Western diet (Nunemaker et al., 2008). The role of 12-LO as a key mediator in the development of autoimmune diabetes is supported by studies of 12-LO deletion in the type 1 diabetes mouse model, NOD mice. "
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    ABSTRACT: Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP-1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes.
    Molecular and Cellular Endocrinology 03/2012; 358(1):88-95. DOI:10.1016/j.mce.2012.03.004 · 4.24 Impact Factor
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    • "The 12-LO-knouckout mouse has been a useful model to study the role of 12-LO and its metabolites on adipose tissue function. Remarkably, this mouse is resistant to inflammatory effects induced by a high calorie (western) diet (Nunemaker et al., 2008): it exhibited a lower macrophage count in the visceral adipose tissue in comparison with the wild-type mouse fed on the same diet. Interestingly, this high calorie diet increased fat accumulation and adipocyte size in both types of mice; but, despite the increased fat storage, only the adipose tissues of the 12-LO-KO mice maintained a non-inflammatory environment and did not attract or activate macrophages. "
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    ABSTRACT: Adipose tissues function as the primary storage compartment of fatty acids and as an endocrine organ that affects peripheral tissues. Many of adipose tissue-derived factors, often termed adipokines, have been discovered in recent years. The synthesis and secretion of these factors vary in different depots of adipose tissues. Excessive lipid accumulation in adipocytes induces inflammatory processes by up-regulating the expression and release of pro-inflammatory cytokines. In addition, activated macrophages in the obese adipose tissue release inflammatory cytokines. Adipose tissue inflammation has also been linked to an enhanced metabolism of polyunsaturated fatty acids (PUFAs). The non-enzymatic peroxidation of PUFAs and of their 12/15-lipoxygenase-derived hydroperoxy metabolites leads to the generation of the reactive aldehyde species 4-hydroxyalkenals. This review shows that 4-hydroxyalkenals, in particular 4-hydroxynonenal, play a key role in lipid storage homeostasis in normal adipocytes. Nonetheless, in the obese adipose tissue an increased production of 4-hydroxyalkenals contributes to the inflamed phenotype.
    Archives of Physiology and Biochemistry 03/2011; 117(3):131-9. DOI:10.3109/13813455.2011.557387
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