Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice.
Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88-94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t(1/2) for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes.
Mody
Nimesh
N
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Graham
Timothy E
TE
Tsuji
Yuki
Y
Yang
Qin
Q
Kahn
Barbara B
BB
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D005260:Female; D007275:Injections, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000097:blood; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D011228:Prealbumin / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism / Q000493:pharmacokinetics*
D004041:Dietary Fats; D020738:Leptin; D011228:Prealbumin; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma