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: 3.79). 10/2008; 295(5):E1065-75. DOI: 10.1152/ajpendo.90371.2008
Source: PubMed


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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    • "12/15-LO is expressed in both rodent and human islets and its expression and activity are upregulated in HF diet-induced obese mice [54]. Recent studies have shown that 12-LO knockout mice are resistant to islet β-cell damage induced by HF feeding [54] or low-dose STZ administration [55], suggesting that this enzyme plays a crucial role in mediating metabolic stress-induced pancreatic β-cell damage. Baicalein has been shown to be a potent inhibitor of 12/15-LO [56]. "
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    ABSTRACT: In both type 1 (T1D) and type 2 diabetes (T2D), the deterioration of glycemic control over time is primarily caused by an inadequate mass and progressive dysfunction of β-cell, leading to the impaired insulin secretion. Here, we show that dietary supplementation of baicalein, a flavone isolated from the roots of Chinese herb Scutellaria baicalensis, improved glucose tolerance and enhanced glucose-stimulated insulin secretion (GSIS) in high-fat diet (HFD-) induced middle-aged obese mice. Baicalein had no effect on food intake, body weight gain, circulating lipid profile, and insulin sensitivity in obese mice. Using another mouse model of type 2 diabetes generated by high-fat diet (HFD) feeding and low doses of streptozotocin injection, we found that baicalein treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in these middle-aged obese diabetic mice, which are associated with the improved islet β-cell survival and mass. In the in vitro studies, baicalein significantly augmented GSIS and promoted viability of insulin-secreting cells and human islets cultured either in the basal medium or under chronic hyperlipidemic condition. These results demonstrate that baicalein may be a naturally occurring antidiabetic agent by directly modulating pancreatic β-cell function.
    International Journal of Endocrinology 07/2014; 2014:846742. DOI:10.1155/2014/846742 · 1.95 Impact Factor
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    • "However, Leukocyte-12-LOX (12/15-LOX) appears to be a significant player in modulating adipocyte function in vivo in diet-induced mouse models of obesity. In a comparative study of 12/15-LOX knockout mice with C57BL6/J mice fed either a standard chow or high-fat “Western” type diet revealed that 12/15-LOX is the primary enzyme generating the 12(S)-HETE products under obese conditions (Nunemaker et al., 2008). The increased 12/15-LOX activity coincided with increased inflammation both systemically and in epididymal adipose tissue. "
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    ABSTRACT: The prevalence of cardiovascular disease (CVD), the leading cause of death in the US, is predicted to increase due to the shift in age of the general population and increase in CVD risk factors such as obesity and diabetes. New therapies are required to decrease the prevalence of CVD risk factors (obesity and diabetes) as well as reduce atherothrombosis, the major cause of CVD related mortality. Oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids, play a role in the progression of CVD risk factors and thrombosis. Aspirin, a cyclooxygenase-1 inhibitor, decreases atherothrombotic associated mortality by 25%. These potent effects of aspirin have shown the utility of modulating oxylipin signaling pathways to decrease CVD mortality. The role of many oxylipins in the progression of CVD, however, is still uncertain or controversial. An increased understanding of the role oxylipins play in CVD risk factors and thrombosis could lead to new therapies to decrease the prevalence of CVD and its associated mortality.
    Frontiers in Pharmacology 01/2014; 4:176. DOI:10.3389/fphar.2013.00176 · 3.80 Impact Factor
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    • "This is interesting as 15-LOX and its metabolites have been shown to be crucial in metabolic syndrome [52–54]. Indeed, high-fat-fed mice showed an increase in the expression of 15-LOX which is a nonheme iron dioxygenase that catalyzes the hydroperoxidation of polyunsaturated fatty acids [52–54]. In addition, adipocyte specific deletion of 15-LOX corrected the pathological and molecular features of metabolic syndrome [53]. "
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    ABSTRACT: Studying ultrastructural changes could reveal novel pathophysiology of obese-asthmatic condition as existing concepts in asthma pathogenesis are based on the histological changes of the diseased airway. While asthma is defined in functional terms, the potential of electron microscopy (EM) in providing cellular and subcellular detail is underutilized. With this view, we have performed transmission EM in the lungs from allergic mice that show key features of asthma and high-fat- or high-fructose-fed mice that mimicked metabolic syndrome to illustrate the ultrastructural changes. The primary focus was epithelial injury and metaplasia, which are cardinal features of asthma and initiate airway remodeling. EM findings of the allergically inflamed mouse lungs correlate with known features of human asthma such as increased mitochondria in airway smooth muscle, platelet activation and subepithelial myofibroblasts. Interestingly, we found a clear and unambiguous evidence to suggest that ciliated cells can become goblet cells using immunoelectron microscopy. Additionally, we show for the first time the stressed mitochondria in the bronchial epithelia of high-fat- or high-fructose-fed mice even without allergen exposure. These results may stimulate interest in using EM in understanding novel pathological mechanisms for different subtypes of asthma including obese asthma.
    09/2013; 2013(2):261297. DOI:10.1155/2013/261297
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