title: 12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets.
abstract: High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.
authors: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA stersey@iu.edu rmirmira@iu.edu.
authors: Sarah A
authors: SA
authors: Tersey
authors: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Bernhard
authors: B
authors: Maier
authors: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Yurika
authors: Y
authors: Nishiki
authors: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Aarthi V
authors: AV
authors: Maganti
authors: Department of Medicine and Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, USA.
authors: Jerry L
authors: JL
authors: Nadler
authors: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA stersey@iu.edu rmirmira@iu.edu.
authors: Raghavendra G
authors: RG
authors: Mirmira
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006965:Hyperplasia / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1
chemical_list: D016207:Cytokines; D051267:NF-E2-Related Factor 2; D005979:Glutathione Peroxidase; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse