Defects in the ability of fat cells to transport glucose are linked to insulin resistance in muscle and liver. Retinol binding protein 4 (RBP4) now comes to the fore as a new adipokine, linking glucose uptake in adipocytes with systemic insulin sensitivity. Liver, skeletal muscle and adipose tissue are the three major targets for the metabolic actions of insulin. Insulin regulates glucose homeostasis by reducing hepatic glucose output and by increasing the rate of glucose uptake by skeletal muscle and adipose tissue.

Tamori Y, Sakaue H, Kasuga M. RBP4, an unexpected adipokine. Nat Med. 2006;12(1):30-1.

CONTEXT: Administration of retinol-binding protein 4 (RBP-4) impairs insulin sensitivity in animals, and elevated serum concentrations have been associated with insulin resistance in humans.
OBJECTIVE: We have therefore studied whether weight loss influences RBP-4. Patients and Methods: Fasting serum concentrations of RBP-4 were measured before and 6 months after gastric banding surgery in 33 morbidly obese patients aged 40±11 years with a body mass index (BMI) of 46±5 kg/m2. Fourteen healthy subjects aged 29±5 years with a BMI<25 kg/m2 served as controls. To characterize the association of weight loss with central and peripheral appetite regulation, the signalling protein agouti-related protein (AGRP), the orexigenic hormone ghrelin and its recently identified antagonist obestatin was determined.
RESULTS: At baseline RBP-4 levels were markedly higher in obese than in lean subjects (2.7±0.5 ng/ml vs. 0.9±0.5 ng/ml, p<0.001). In contrast, AGRP and obestatin were lower in obese subjects compared with lean controls (all p<0.001). Six months after gastric banding BMI was reduced to 40±5 kg/m2, RBP-4 to 2.0±0.7 ng/ml, and AGRP increased from1.8±1.1 to 3.4±1.1 ng/ml, ghrelin from 93±58 pg/ml to 131±70 pg/ml, and obestatin from 131±52 to 173±35 pg/ml (all p< 0.05). Individual changes of RBP-4 were associated with changes of BMI (r=0.72), the homeostasis model assessment (HOMA) insulin resistance-index (r=0.53) and total cholesterol (r=0.42, for all p<0.05). Conclusion: Reductions in circulating RBP-4 may contribute to improved insulin resistance in morbidly obese subjects after weight loss. This is accompanied by favourable changes in appetite-regulating hormones which might support the sustained weight loss after obesity surgery.

Haider DG, Schindler K, Prager G, et al. Serum retinol-binding protein 4 is reduced after weight loss in morbidly obese subjects. J Clin Endocrinol Metab. 2007;92(3):1168-71.

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

Yang Q, Graham TE, Mody N, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436(7049):356-62.

Adipokines are hormones that signal changes in fatty-tissue mass and energy status so as to control fuel usage. A fat-derived adipokine that binds to vitamin A provides a new link between obesity and insulin resistance.

The worldwide epidemic of obesity has been accompanied by a surge in the incidence of diabetes1. Normally, control of blood glucose levels depends on the efficient action of insulin, which stimulates uptake of glucose from the blood and slows its output from the liver.

Deborah M. Muoio1 and Christopher B. Newgard1. Metabolism: A is for adipokine. Nature 436, 337-338 (21 July 2005) | doi: 10.1038/436337a