Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity

Abstract

OBJECTIVEThe 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 RESULTSUnder 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.CONCLUSIONSLipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue.

Liver-Restricted Repin1 Deficiency Improves Whole-Body Insulin Sensitivity, Alters Lipid Metabolism, and Causes Secondary Changes in Adipose Tissue in Mice

“…This hypothesis is supported by data that Lcn2 deficiency protects mice from developing aging-and obesity-induced insulin resistance by modulating insulin resistance factors in adipose tissue (34). Lcn2-disrupted mice are partly protected from HFD-induced insulin resistance.…”

“…In contrast to our observation marked Lcn2 deficiency leads to enlarged adipocytes and improved adipose tissue function, which has been related to reduced inflammation in adipose tissue of these mice (34). We cannot exclude that changes in adipose tissue of LRep1 2/2 mice are at least in part mediated by reduced inflammatory activation in adipose tissue.…”

Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control

“…Thus, the genetic disruption of MCP-1 receptor gene, 48 transport protein lipocalin-2, 49 or disruption of the gene for a component of extracellular matrix, namely Sex-specific effects of high-fat feeding in mice D Medrikova et al collagen VI, 17 resulted in larger adipocytes, lower adipose tissue inflammation and attenuated insulin resistance in male mice fed the HF diet. These data suggest a role for extracellular matrix in the mechanisms underlying adipocyte death, due to restriction of adipocytes' enlargement and shear stress.…”

Obesity, inflammation, and insulin resistance

“…Several inflammatory stimuli, such as lipopolysaccharide and IL-1, can promote Lcn2 expression and secretion. Pro-inflammatory transcription factor NF-κB activates Lcn2 expression by binding to the promoter region of gene Lcn2, suggesting its involvement in the inflammatory response (Wang et al, 2007;Law et al, 2010;El-Mesallamy et al, 2012;Kamata et al, 2012).…”