Aims/hypothesis: We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 (-/-)) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function.
Methods: Alox5 (-/-) and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments.
Results: Beginning at 12 weeks of age, Alox5 (-/-) mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p<0.05). Although Alox5 (-/-) mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed that Alox5 (-/-) mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm(2) islet (p<0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 (-/-) islets were significantly lower than in WT islets (p<0.05) and accompanied by a three- to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05).
Conclusions/interpretation: These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.