Retinol-Binding Protein 4 in Human Obesity

Abstract

Studies in mice suggest that adipocytes serve as glucose sensors and regulate systemic glucose metabolism through release of serum retinol-binding protein 4 (RBP4). This model has not been validated in humans. RBP4 was highly expressed in isolated mature human adipocytes and secreted by differentiating human adipocytes. In contrast to the animal data, RBP4 mRNA was downregulated in subcutaneous adipose tissue of obese women, and circulating RBP4 concentrations were similar in normal weight, overweight, and obese women (n ‫؍‬ 74). RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable. Five percent weight loss slightly decreased adipose RBP4 expression but did not influence circulating RBP4. In another set of experiments, we stratified patients (n ‫؍‬ 14) by low or high basal fasting interstitial glucose concentrations, as determined by the microdialysis technique. Venous glucose concentrations were similar throughout oral glucose tolerance testing, and basal RBP4 expression in adipose tissue and serum RBP4 concentrations were similar in the groups with higher and lower interstitial glucose levels. Our findings point to profound differences between rodents and humans in the regulation of adipose or circulating RBP4 and challenge the notion that glucose uptake by adipocytes has a dominant role in the regulation of RBP4. Diabetes 55:

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

“…In that study, RBP4 serum levels were not different between lean, overweight and obese subjects. In addition, crosssectional and weight-loss studies did not show any relationships between the HOMA-IR and adipose RBP4 expression or with circulating RBP4 concentrations [14]. This appears to be in contrast to other recently published data, which provide evidence for a connection between RBP4 and the glucose disposal rate as detected in clamp studies in men and women with type 2 diabetes, obese patients without diabetes and even in healthy subjects with a family history of diabetes [1].…”

“…In addition, statistical analyses of collinearity revealed that even the significant independent association between BMI and RBP4 in patients with type 2 diabetes (Table 2) crucial anthropometric characteristic in type 2 diabetes and thus remained in the model in order to achieve applicable clinical comparability; no alterations of the significant associations were present after exclusion of BMI (data not shown). Our findings are in accordance with recent published data [14] regarding the role of RBP4 in human obesity. In that study, RBP4 serum levels were not different between lean, overweight and obese subjects.…”

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…However, brain RBP4 protein levels tended to be higher in APP/PSEN1 mice on chow diet and significantly higher in PSEN1 and APP/PSEN1 mice on HFD, suggesting that increased RBP4 levels may be another mechanism by which Alzheimer's disease genotype predisposes to diet-induced glucose intolerance. RBP4 is an adipokine that was recently found to be elevated in insulin-resistant states as well as in obesity in mice [23,39,40] and humans [41][42][43][44], although not all studies have reported this [24,45]. These data suggest that there are early markers of insulin resistance already present with the APP genotype, making these mice more susceptible to the effects of HFD feeding and associated insulin resistance.…”

Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children: a review

“…101 In humans, serum RBP4 concentrations may be correlated with obesity and insulin resistance. [102][103][104] RBP4 is the specific transport protein for serum retinol (SR), and alterations of retinol intake and vitamin A status affect hepatic release of RBP4 and circulating RBP4. 105 In addition, increased subclinical inflammation is a characteristic of obesity and RBP4 is a negative acute-phase protein.…”

“…In contrast, other studies have not found a link between RBP and obesity and/or insulin resistance in adults. 110,111 For example, Janke et al 104 reported no differences in serum RBP4 among normal, overweight and obese women, and found RBP4 mRNA was downregulated in adipose tissue of obese women. Studies performed before RBP4 were identified as an adipokine investigated vitamin A status in adults with type 2 diabetes and reported equivocal results.…”