Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity
Open Access
- 12 January 2010
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 59 (4), 872-882
- https://doi.org/10.2337/db09-1541
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. 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-α (TNF-α), 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-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α 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-α levels in adipose tissue.Keywords
This publication has 50 references indexed in Scilit:
- 12/15‐Lipoxygenase Products Induce Inflammation and Impair Insulin Signaling in 3T3‐L1 AdipocytesObesity, 2009
- Lipocalin 2 promotes breast cancer progressionProceedings of the National Academy of Sciences of the United States of America, 2009
- 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by western dietAmerican Journal of Physiology-Endocrinology and Metabolism, 2008
- Intramuscular lipid metabolism, insulin action, and obesityIUBMB Life, 2008
- The Role of Lipocalin 2 in the Regulation of Inflammation in Adipocytes and MacrophagesMolecular Endocrinology, 2008
- Lipocalin-2 Is an Inflammatory Marker Closely Associated with Obesity, Insulin Resistance, and Hyperglycemia in HumansClinical Chemistry, 2007
- Adipocytokines: mediators linking adipose tissue, inflammation and immunityNature Reviews Immunology, 2006
- Neutralization of tumor necrosis factor-α reverses insulin resistance in skeletal muscle but not adipose tissueAmerican Journal of Physiology-Endocrinology and Metabolism, 2004
- Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.JCI Insight, 1995
- Comparison of TOBEC-derived total body fat with fat pad weightsPhysiology & Behavior, 1995