Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice

Area of Science:

• Metabolism
• Immunology
• Endocrinology

Background:

• The 12-lipoxygenase (12LO) pathway is a potential therapeutic target for islet dysfunction, adipose tissue inflammation, and insulin resistance.
• Optimal pre-clinical models for studying selective 12LO inhibitors are needed.

Purpose of the Study:

• To characterize the temporal expression of 12LO isoforms and metabolite production in pancreatic islets and adipose tissue (AT) of C57BLKS/J-db/db obese diabetic mice during the pre-diabetic stage.
• To establish a therapeutic window for intervention with selective lipoxygenase inhibitors.

Main Methods:

• Utilized C57BLKS/J-db/db mice at 8 and 10 weeks of age.
• Assessed 12LO isoform expression (protein and gene) in pancreatic islets and AT.
• Quantified 12- and 15-hydroperoxytetraeicosanoid acids (HETEs) in islets and AT.
• Performed immunohistochemistry to analyze islet morphology and cell types.

Main Results:

• A significant increase in 12/15LO protein expression was observed in pancreatic islets of 10-week-old db-/- mice compared to 8-week-old counterparts.
• Increased 12/15LO expression in islets paralleled a decline in islet number.
• A 2-3 fold increase in 12(S)-HETE and other HETEs was detected in islets, correlating with 12/15LO expression.
• Platelet 12LO gene expression and HETE levels were elevated in AT and stromal vascular fraction (SVF).

Conclusions:

• The db/db mouse model is suitable for investigating 12/15LO inhibitors in the context of inflammatory type 2 diabetes.
• A narrow therapeutic intervention window exists before 8 weeks of age in this model.