Serum retinol-binding protein 4 (RBP4) is the main vitamin A (retinol) transport protein in the blood. Many clinical studies link elevated serum RBP4 levels to metabolic diseases including obesity, insulin-resistance, type 2 diabetes (T2D), and cardiovascular disease. Large epidemiologic studies demonstrate that elevated circulating RBP4 levels are a biomarker for these diseases. Elevation of RBP4 levels causes insulin resistance, whereas lowering RBP4 levels improves insulin sensitivity. Serum RBP4 levels are elevated in pre-diabetic people even before overt hyperglycemia occurs. The possibility that RBP4 causes insulin resistance in humans is supported by genetic data.
The immune system plays an important role in obesity-related insulin resistance. The mechanism for RBP4-induced insulin resistance involves inflammation. In humans, RBP4 levels in serum and adipose tissue strongly correlate with subclinical inflammation, including pro-inflammatory cytokine levels. RBP4 impairs insulin signaling in adipocytes indirectly by inducing pro-inflammatory cytokine production from macrophages through the c-Jun N-terminal protein kinase-dependent pathway. Transgenic mice overexpressing RBP4 have increased numbers of adipose tissue macrophages and CD4 T-cells. Transfer of antigen-presenting cells treated with RBP4 ex vivo into normal mice is sufficient to cause insulin resistance. Thus, RBP4-mediated activation of the innate immune system elicits an adaptive immune response resulting in insulin resistance. These effects are not mediated through a known RBP4 receptor, STRA6, but involve Toll-Like Receptor 4. Blockade of antigen presentation with CTLA4-Ig (cytotoxic T-lymphocyte associated antigen 4-Ig; a drug used to treat immune-mediated diseases) is sufficient to improve systemic insulin resistance and adipose tissue inflammation in RBP4-overexpressing mice. This indicates that the RBP4-induced insulin resistance associated with obesity could be improved by blocking antigen presentation and subsequent T-cell activation. Alternatively, insulin resistance and adipose inflammation could be ameliorated by lowering serum RBP4 levels.