12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets

Sarah A. Tersey, Bernhard Maier, Yurika Nishiki, Aarthi V. Maganti, Jerry L. Nadler, Raghavendra G. Mirmira

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3735-3745
Number of pages11
JournalMolecular and cellular biology
Volume34
Issue number19
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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