Adipocytokines and Insulin Resistance

Adipocytokines and Insulin Resistance The possible role of lipocalin-2, retinol binding protein-4, and adiponectin Eduardo Esteve , MD, PHD , Wifredo Ricart , MD and José Manuel Fernández-Real , MD, PHD From the Unit of Diabetes, Endocrinology and Nutrition, Biomedical Research Institute of Girona, and CIBEROBN Fisiopatología de la Obesidad y Nutrición, Girona, Spain. Corresponding author: J.M. Fernández-Real, jmfernandezreal.girona.ics{at}gencat.cat . It is well known that adipocytes and resident macrophages that have migrated to adipose tissue produce and secrete a variety of biologically active mediators (adipocytokines), which are thought to contribute to the development of insulin resistance, type 2 diabetes, and cardiovascular disease ( 1 ). The abnormal function of adipocytes may play an important role in the development of a chronic low-grade proinflammatory state associated with obesity ( 2 ). For example, adipocyte hypertrophy appears to lead to an imbalance between pro- and anti-inflammatory adipokines. The secretion of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and granulocyte colony–stimulating factor have been positively correlated with adipocyte size. Adipose tissue is an important inflammatory source in obesity and type 2 diabetes, not only because of cytokines produced from the adipocyte itself, but also because of infiltration by proinflammatory macrophages ( 3 ). Not only do adipocytes, but also adipose tissue macrophage numbers, increase with obesity and participate in inflammatory pathways of obese individuals. Macrophages from adipose tissue are responsible for almost all adipose tissue tumor necrosis factor (TNF)-α and significant amounts of IL-6 production. Macrophages migrating to adipose tissue in response to high-fat feeding overexpress proinflammatory cytokines. Different cytokines synthesized by adipocytes or by macrophages from adipose tissue may induce insulin resistance, such as IL-6, TNF-α, leptin, resistin, adiponectin, retinol binding protein-4 (RBP4), or lipocalin-2 (LCN2). This review focuses on the latter adipocytokines, hinting at their role in obesity-associated insulin resistance. LCN2 LCN2 (or neutrophil gelatinase-associated lipocalin) is a recently identified adipokine that belongs to the superfamily of lipocalins (such as RBP4), which seems to affect glucose metabolism and insulin sensitivity ( 4 ). LCN2 protein has been implicated in diverse actions, such as apoptosis and innate immunity, and