Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Diabetologia. 2008 Jun;51(6):978-88. doi: 10.1007/s00125-008-1002-3. Epub 2008 Apr 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Proteins
  • Adipose Tissue / enzymology*
  • Adipose Tissue / physiology*
  • Animals
  • Arachidonate 5-Lipoxygenase / deficiency
  • Arachidonate 5-Lipoxygenase / genetics
  • Blood Glucose / metabolism
  • Body Composition
  • Body Weight
  • Carrier Proteins / genetics*
  • Crosses, Genetic
  • Female
  • Glucose Tolerance Test
  • Humans
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Leptin / blood
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreas / enzymology*
  • RNA / genetics
  • RNA / isolation & purification
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Sex Characteristics
  • Tissue Donors


  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Alox5ap protein, mouse
  • Blood Glucose
  • Carrier Proteins
  • Insulin
  • Leptin
  • Membrane Proteins
  • RNA, Small Interfering
  • RNA
  • Arachidonate 5-Lipoxygenase