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

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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
Pages (from-to)3735-3745
Number of pages11
JournalMolecular and Cellular Biology
Volume34
Issue number19
DOIs
StatePublished - 2014

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Arachidonate 12-Lipoxygenase
Islets of Langerhans
Oxidative Stress
Obesity
High Fat Diet
Knockout Mice
Antioxidants
Fats
Enzymes
Body Fat Distribution
Arachidonic Acid
Transcriptional Activation
Weight Gain
Hyperplasia
Pancreas
Transcription Factors
Macrophages
Insulin
Inflammation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets. / Tersey, Sarah A.; Maier, Bernhard; Nishiki, Yurika; Maganti, Aarthi V.; Nadler, Jerry L.; Mirmira, Raghu.

In: Molecular and Cellular Biology, Vol. 34, No. 19, 2014, p. 3735-3745.

Research output: Contribution to journalArticle

Tersey, Sarah A. ; Maier, Bernhard ; Nishiki, Yurika ; Maganti, Aarthi V. ; Nadler, Jerry L. ; Mirmira, Raghu. / 12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 19. pp. 3735-3745.
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