Serum levels of retinol-binding protein 4 and risk of colon adenoma.

Obesity is now considered as a convincing and probable cause for colorectal neoplasia (World Cancer Research Fund 2011). Insulin resistance is a key mechanism relating obesity to colon carcinogenesis (Giovannucci 2001). Supporting evidence for this notion includes data from a number of epidemiological studies demonstrating the risk association of colon cancer and adenoma with insulin resistance-associated biomarkers, such as insulin, insulinlike growth factors, adipokines (e.g. leptin and adiponectin), and inflammatory cytokines (e.g. IL6 and TNFa) (Giovannucci 2001, Sandhu et al. 2002, Ortiz et al. 2012). Retinol-binding protein 4 (RBP4), a recently identified adipokine, has been shown to potentially have a causative effect on the development of insulin resistance (Yang et al. 2005, Graham et al. 2006). RBP4 increases expression of the glucose transporter, GLUT4 (SLC2A4), which facilitates the rate-limiting step in glucose uptake by skeletal muscle and adipocytes. In adipose tissue-specific Glut4 knockout (adipose-Glut4) mice, secretion of RBP4 by adipocytes is greatly enhanced. Increased circulating levels of RBP4 suppress phosphoinositide-3-kinase in muscle cells, and in the liver, stimulate the expression of phosphoenolpyruvate carboxykinase (PEPCK), inducing systemic insulin resistance. Treatment of adipose-Glut4 mice with rosiglitazone, an insulin sensitizer, reduced the elevated RBP4 mRNA levels in adipose tissue and completely normalized the serum RBP4 levels (Yang et al. 2005). In humans, subcutaneous adipocyte GLUT4 protein levels correlated positively with the rate of glucose disposal and negatively with serum levels of RBP4 (Graham et al. 2006). Despite the emerging evidence for a causal relationship of RBP4 to insulin resistance, no previous study has investigated the relationship between RBP4 and colon neoplasia. Therefore, we carried out a cross-sectional study to examine the hypothesis that high levels of RBP4 are associated with an increased risk of colon adenoma.