Retinol Binding Protein 4 Expression in Humans: Relationship to Insulin Resistance, Inflammation, and Response to Pioglitazone

Abstract

Context:Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance. Objective:The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans.Design and Patients: RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients. Setting:The study was conducted at University Hospital and General Clinical Research Center.Intervention: Insulin sensitivity (S I ) was measured, and fat and muscle biopsies were performed. In IGT subjects, these procedures were performed before and after treatment with metformin or pioglitazone. Main Outcome Measures:The relationship between RBP4 expression and obesity, S I , adipose tissue inflammation, and intramyocellular lipid level, and response to insulin sensitizers was measured.Results: RBP4 was expressed predominantly from the adipocyte fraction of SAT. Although SAT RBP4 expression and the plasma RBP4 level demonstrated no significant relationship with body mass index or S I , there was a strong positive correlation between RBP4 mRNA and adipose inflammation (monocyte chemoattractant protein-1 and CD68), and glucose transporter 4 mRNA. Treatment of IGT subjects with pioglitazone resulted in an increase in S I and an increase in RBP4 gene expression in both adipose tissue and muscle, but not in plasma RBP4 level, and the in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA. Conclusions

RBP4: a controversial adipokine

“…In adipose tissue and muscle, insulin-sensitizing agent pioglitazone unexpectedly increased RBP4 gene expression (10). With regard to children, RBP4 levels do not significantly differ between prepubertal and pubertal children, despite the later being significantly more insulin resistant, indicating lack of causal association between insulin resistance and RBP4 serum levels in children and adolescents (68).…”

“…In several studies, circulating RBP4 levels also did not correlate with insulin resistance, impaired glucose tolerance, T2D, or altered insulin secretion (10,72,(74)(75)(76)(77). In adipose tissue and muscle, insulin-sensitizing agent pioglitazone unexpectedly increased RBP4 gene expression (10).…”

“…Several studies found no correlation between circulating RBP4 levels, the level of obesity, and the amount and distribution of adipose tissue (9-11, 35, 72). In addition, several studies found no correlation between RBP4 adipose tissue mRNA expression and serum levels (9,10,44,73).…”

“…In a study focusing on the role of inflammation in RBP4 expression in human adipocytes, RBP4 was unexpectedly downregulated by tumor necrosis factor a (TNFa) (92). While studying the effect of commonly used anti-diabetic medications on RBP4 expression in human adipocytes, surprisingly an upregulation of RBP4 was determined with the use of PPARg agonists troglitazone and pioglitazone (10,92). Metformin had no effect on the expression of RBP4 (92).…”

“…Retinol binding protein 4 (RBP4) is a recently identified adipokine (8) that has caused a controversial scientific discussion on whether and how it links to adiposity, insulin resistance, and type 2 diabetes (T2D) (9)(10)(11).…”