title: Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity.
abstract: OBJECTIVE
  The proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms.
  
  
  RESULTS
  Under conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-alpha (TNF-alpha), a critical insulin resistance-inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-alpha production in fat tissues. Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-alpha expression induced by lipocalin-2. Moreover, treatment with TNF-alpha neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice.
  
  
  CONCLUSIONS
  Lipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-alpha levels in adipose tissue.
authors.affiliation: Department of Pharmacology and Pharmacy, the University of Hong Kong, Hong Kong, China.
authors.forename: Ivy K M
authors.initials: IK
authors.lastname: Law
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Jacky T C
authors.initials: JT
authors.lastname: Liu
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000172:deficiency*; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008055:Lipids / Q000097:blood; D000071068:Lipocalin-2; D054834:Lipocalins; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000517:prevention & control; D015513:Oncogene Proteins / Q000172:deficiency*; D054411:Receptors, Leptin / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D054411:Receptors, Leptin; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D005947:Glucose