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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    • "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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    • "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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