Lipocalins and Insulin Resistance: Etiological Role of Retinol-Binding Protein 4 and Lipocalin-2?

The prevalence of type 2 diabetes is increasing dramatically worldwide. Excess adiposity is an important contributor to the development of type 2 diabetes and cardiovascular diseases (1). Insulin resistance, inflammation, hypertension, and dyslipidemia, components of the metabolic syndrome, have been implicated in the effects of adiposity on type 2 diabetes and cardiovascular diseases, but the mechanisms responsible for these detrimental effects of adiposity have not been fully elucidated. Two paradigms are currently areas of intense study: one focused on ectopic fat and the other on the endocrine function of adipose tissue (2). Ectopic fat is present in nonadipose tissues such as the liver, muscle, and probably pancreatic β-cells. Both lipodystrophy (failure to develop adipose tissue) and obesity with full adipose cells are characterized by a lack of fat-storage capacity, resulting in overflow to other tissues of triglycerides and free fatty acids in the form of ectopic fat. Normal physiological processes can be disrupted by this ectopic fat, leading to insulin resistance and impaired insulin secretion. The endocrine function of adipose tissue is an important regulatory process throughout the body that is carried out by signaling proteins secreted by adipose tissue. These signaling proteins are called adipocytokines or adipokines, and they include leptin, adiponectin, resistin, tumor necrosis factor-α, and interleukin-6. Members of the lipocalin family of proteins have large sequence differences but share a common tertiary structure formed by segments termed lipocalin folds (3). Lipocalin folds consist of 8 antiparallel β-sheets that surround a hydrophobic pocket and allow lipocalins to function as transport or carrier proteins. Several human lipocalins have been identified, including retinol-binding protein 4 (RBP4), which has recently been added to the list of adipokines that may link obesity and insulin resistance (4)(5). In this issue of Clinical Chemistry , Dr. Wang and …