The Adipokine Lipocalin 2 Is Regulated by Obesity and Promotes Insulin Resistance

Abstract

OBJECTIVE-We identified lipocalin 2 (Lcn2) as a gene induced by dexamethasone and tumor necrosis factor-␣ in cultured adipocytes. The purpose of this study was to determine how expression of Lcn2 is regulated in fat cells and to ascertain whether Lcn2 could be involved in metabolic dysregulation associated with obesity. RESEARCH DESIGN AND METHODS-We examined Lcn2expression in murine tissues and in 3T3-L1 adipocytes in the presence and absence of various stimuli. We used quantitative Western blotting to observe Lcn2 serum levels in lean and obese mouse models. To assess effects on insulin action, we used retroviral delivery of short hairpin RNA to reduce Lcn2 levels in 3T3-L1 adipocytes.RESULTS-Lcn2 is highly expressed by fat cells in vivo and in vitro. Expression of Lcn2 is elevated by agents that promote insulin resistance and is reduced by thiazolidinediones. The expression of Lcn2 is induced during 3T3-L1 adipogenesis in a CCAAT/enhancer-binding protein-dependent manner. Lcn2 serum levels are elevated in multiple rodent models of obesity, and forced reduction of Lcn2 in 3T3-L1 adipocytes improves insulin action. Exogenous Lcn2 promotes insulin resistance in cultured hepatocytes. T he worldwide epidemic of obesity and type 2 diabetes has focused attention on adipocyte biology and the role of adipose tissue in the integration of systemic metabolism (1). The discovery of leptin more than a decade ago established a paradigm in which secreted proteins from adipocytes coordinate energy balance and glucose homeostasis (2,3). Since that initial discovery, the number of adipocytederived signaling molecules has grown ever larger, and the term adipokine was coined to reflect that many of these molecules exert positive or negative actions on inflammation. Several adipokines promote insulin sensitivity, including leptin (2), adiponectin (4), and visfatin (5), while others induce insulin resistance, such as resistin (6) and retinol binding protein (RBP)4 (7). CONCLUSIONS-Lcn2Lipocalin 2 (Lcn2)-also known as neutrophil gelatinase-associated lipocalin, siderocalin, and 24p3-is a member of a large superfamily of proteins that includes RBP4. Lipocalins are small generally secreted proteins with a hydrophobic ligand binding pocket (8). Known ligands for lipocalins include retinol, steroids, odorants, pheromones, and, in the case of Lcn2, siderophores (9). Siderophores are small molecules used by bacteria to poach iron from their hosts, a necessary cofactor for the growth of some pathogens. Lcn2 is used by the mammalian-innate immune system to sequester siderophore and thus deprive the bacteria of iron. Mice lacking Lcn2 appear normal but die when exposed to siderophorerequiring strains of bacteria in quantities that are cleared easily by wild-type mice (10,11). Lcn2 can thus be considered an iron transport protein, and it has been implicated in the apoptotic induction of pro-B-cells (12) and in the biology of the genitourinary system, both as a developmental factor and as a protective mechanism in renal ischemia (13).In this s...

Serum concentrations of atherogenic proteins neutrophil gelatinase-associated lipocalin and its complex with matrix metalloproteinase-9 are significantly lower in women with polycystic ovary syndrome: hint of a protective mechanism?

“…NGAL or lipocalin 2 is thought to be an acute phase protein whose expression is up-regulated in humans, typically in epithelial cells, under diverse inflammatory conditions (24). Additionally, a role of NGAL as a mediator of insulin resistance has been recently suggested (25,26). Overall, the full functional repertoire of NGAL remains to be elucidated.…”

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

“…Because of the unique structure, the lipocalins function as efficient transporters for a number of different hydrophobic ligands in extracellular milieus, including a variety of retinoids, fatty acids, biliverdin, pheromones, porphyrins, odorants, steroids, and iron (32). In vitro, it was shown that exogenous Lcn2 promotes insulin resistance in cultured hepatocytes (33). It is likely that Lcn2 as retinoic acid could potentially be involved in or mediate lipid storage effects in both liver and adipose tissue.…”

Obesity, inflammation, and insulin resistance

“…Lcn2 expression is increased by agents promoting insulin resistance, and reduced by thiazolidinediones, indicating a role in insulin resistance in obesity (Yan et al, 2007;Fried, Greenberg, 2012). Furthermore, high Lcn2 levels are associated with a decline in pancreatic β-cell function in diabetic patients (El-Mesallamy et al, 2012).…”