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

The Adipokine Lipocalin 2 Is Regulated by Obesity and Promotes Insulin Resistance Qing-Wu Yan 1 , Qin Yang 1 , Nimesh Mody 1 , Timothy E. Graham 1 , Chung-Hsin Hsu 1 , Zhao Xu 1 , Nicholas E. Houstis 2 , Barbara B. Kahn 1 and Evan D. Rosen 1 2 1 Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 2 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts Address correspondence and reprint requests to Evan D. Rosen, MD, PhD, Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02115. E-mail: erosen{at}bidmc.harvard.edu Abstract OBJECTIVE— We identified lipocalin 2 ( Lcn2 ) as a gene induced by dexamethasone and tumor necrosis factor-α 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 Lcn2 expression 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. CONCLUSIONS— Lcn2 is an adipokine with potential importance in insulin resistance associated with obesity. C/EBP, CCAAT/enhancer-binding protein Dex, dexamethasone DMEM, Dulbecco's modified Eagle's medium FBS, fetal bovine serum PPAR, peroxisome proliferator–activated receptor RBP, retinol binding protein shRNA, short hairpin RNA SVC, stromal vascular cell SVF, stromal vascular factor TNF, tumor necrosis factor WAT, white adipose tissue Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 July 2007. DOI: 10.2337/db07-0007. E.D.R. is listed as an inventor on a patent applicati