Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice
Autor: | Vijay Gottipati, Anna Marley, William L. McPheat, Bronson A. Haynes, Lindsey Glenn, Jerry L. Nadler, Göran I. Hansson, Ryan W. Huyck, Anca D. Dobrian |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Physiology Mice Obese Adipose tissue Context (language use) Inflammation Type 2 diabetes Arachidonate 12-Lipoxygenase Biochemistry Prediabetic State Mice 03 medical and health sciences Insulin resistance Insulin-Secreting Cells Internal medicine medicine Animals Arachidonate 15-Lipoxygenase Lipoxygenase Inhibitors Pharmacology geography geography.geographical_feature_category business.industry Pancreatic islets Cell Biology Stromal vascular fraction medicine.disease Islet Enzyme Activation Isoenzymes 030104 developmental biology Endocrinology medicine.anatomical_structure Diabetes Mellitus Type 2 medicine.symptom business |
Zdroj: | Prostaglandins & Other Lipid Mediators. 136:23-32 |
ISSN: | 1098-8823 |
Popis: | The 12-lipoxygenase (12LO) pathway is a promising target to reduce islet dysfunction, adipose tissue (AT) inflammation and insulin resistance. Optimal pre-clinical models for the investigation of selective12LO inhibitors in this context have not yet been identified. The objective of this study was to characterize the time course of 12LO isoform expression and metabolite production in pancreatic islets and AT of C57BLKS/J-db/db obese diabetic mouse in a pre-diabetic state in order to establish a suitable therapeutic window for intervention with selective lipoxygenase inhibitors. Mice have 2 major 12LO isoforms -the leukocyte type (12/15LO) and the platelet type (p12LO) and both are expressed in islets and AT. We found a sharp increase in protein expression of 12/15LO in the pancreatic islets of 10-week old db-/- mice compared to 8- week old counterparts. Immunohistochemistry showed that the increase in islet 12/15LO parallels a decline in islet number. Analysis of 12- and 15-hydroperoxytetraeicosanoid acids (HETE)s showed a 2-3 fold increase especially in 12(S)-HETE that mirrored the increase in 12/15LO expression in islets. Analysis of AT and stromal vascular fraction (SVF) showed a significant increase of platelet 12LO gene expression along with 12- and 15- HETEs. The data demonstrate that the db/db mouse is a suitable model for investigation of 12/15LO inhibitors in the development of inflammatory mediated type 2 diabetes, with a narrow window of therapeutic intervention prior to 8 weeks of age. |
Databáze: | OpenAIRE |
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