Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice
- Resource Type
- Authors
- Vijay Gottipati; Anna Marley; William L. McPheat; Bronson A. Haynes; Lindsey Glenn; Jerry L. Nadler; Göran I. Hansson; Ryan W. Huyck; Anca D. Dobrian
- Source
- Prostaglandins & Other Lipid Mediators. 136:23-32
- Subject
- 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
- Language
- ISSN
- 1098-8823
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.