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

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

•db/db pre-diabetic mice show tissue specific expression pattern of 12LO isoforms.•The main metabolite produced in islets and visceral adipose tissue is 12(S)-HETE.•The increase in eicosanoid production in islets and adipose tissue parallels the metabolic decline.•db/db strain is a suitable pre-clin...

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Bibliographic Details
Published in:Prostaglandins & other lipid mediators Vol. 136; pp. 23 - 32
Main Authors: Dobrian, Anca D., Huyck, Ryan W., Glenn, Lindsey, Gottipati, Vijay, Haynes, Bronson A., Hansson, Göran I., Marley, Anna, McPheat, William L., Nadler, Jerry L.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-05-2018
Subjects:
Adipocytes
Adipose tissue
Crown-like structures
db/db
Eicosanoids
HETEs
Hyperglycemia
Lipoxygenases
Macrophages
Obesity
Panceratic islets
Pre-diabetes
Resolvins
Stromal vascular fraction
db/db
Obesity
Adipose tissue
Panceratic islets
Eicosanoids
Stromal vascular fraction
Adipocytes
Macrophages
Lipoxygenases
HETEs
Hyperglycemia
Resolvins
Pre-diabetes
Crown-like structures
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Summary:•db/db pre-diabetic mice show tissue specific expression pattern of 12LO isoforms.•The main metabolite produced in islets and visceral adipose tissue is 12(S)-HETE.•The increase in eicosanoid production in islets and adipose tissue parallels the metabolic decline.•db/db strain is a suitable pre-clinical model to test selective LO inhibitors in vivo. 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.
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ISSN:1098-8823
DOI:10.1016/j.prostaglandins.2018.03.003