| First Author | Law IK | Year | 2010 |
| Journal | Diabetes | Volume | 59 |
| Issue | 4 | Pages | 872-82 |
| PubMed ID | 20068130 | Mgi Jnum | J:164340 |
| Mgi Id | MGI:4831113 | Doi | 10.2337/db09-1541 |
| Citation | Law IK, et al. (2010) Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes 59(4):872-82 |
| abstractText | 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. METHODS AND 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. |
