High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans

OBJECTIVE - Retinol-binding protein 4 (RBP4) is an adipokine that induced insulin resistance in mice, and high plasma RBP4 levels were associated with insulin-resistant states in humans. To determine which fat compartments are associated with elevated RBP4 levels in humans, we measured circulating RBP4 in 75 healthy subjects and used state-of-the-art measurements of body fat distribution. RESEARCH DESIGN AND METHODS - Total body, visceral, and subcutaneous abdominal fat were determined by magnetic resonance tomography and liver fat and intramyo-cellular fat by localized proton magnetic resonance spectroscopy. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp and, together with insulin clearance, estimated from the oral glucose tolerance test (OGTT). RESULTS - Adjusted circulating RBP4 correlated negatively with insulin sensitivity (clamp: r = -0.33, P = 0.005 OGTT: r = -0.36, P = 0.002) and positively with parameters in the fasting state as insulin levels (r = 0.35, P = 0.003) and homeostasis model assessment of insulin resistance (r = 0.34, P 0.004). In addition, circulating RBP4 correlated negatively with hepatic insulin clearance (r = 0. 2 5, P = 0. 04). Circulating RBP4 was not associated with total body, visceral, or subcutaneous abdominal fat (all P >= 0.29). Plasma RBP4 levels were also not associated with intramyocellular fat or circulating adiponectin or leptin. In contrast, plasma RBP4 levels correlated positively vith liver fat in cross-sectional (r = 0.27, P = 0.03) and longitudinal (r = 0.37, P = 0.04) analyses. CONCLUSIONS - Circulating RBP4 is not associated with the amount of fat in the classical depots or in the ectopic depots in muscle. However, it correlates positively with liver fat. Furthermore, metabolic parameters support the close relationship between circulating RBP4 with liver fat and, presumably, hepatic insulin resistance.