Serum levels of RBP4 and adipose tissue levels of PTP1B are increased in obese men resident in northeast Scotland without associated changes in ER stress response genes

Background: Retinol-binding protein 4 (RBP4) is an adipokine identified as a marker of insulin resistance in mice and humans. Protein tyrosine phosphatase 1B (PTP1B) expression levels, as well as other genes involved in the endoplasmic-reticulum (ER) stress response, are increased in adipose tissue of obese, high-fat diet fed mice. In this study, we investigated if serum- and/or adipose-tissue RBP4 protein levels, and expression levels of PTP1B and other ER stress-response genes, are altered in obese and obese/diabetic men resident in North East of Scotland.
Methods: We studied three groups of male volunteers: 1) normal/overweight (body mass index (BMI) <30), 2) obese (BMI>30) and 3) obese/diabetic group (BMI>30) controlling their diabetes either by diet or anti-diabetic drug, metformin. We analysed their serum- and adipose-tissue RBP4 protein levels, as well as adipose tissue mRNA expression of PTP1B, BIP (binding immunoglobulinprotein), ATF4 (activated transcription factor 4) and GRP94 (glucose-regulated protein 94), alongside other markers of adiposity (% body fat, leptin, cholesterol, triglycerides) and insulin resistance (oral glucose tolerance tests (OGTT), insulin, HOMA-IR, C-reactive protein (CRP), adiponectin).
Results: We found that obese Scottish subjects had significantly higher serum-RBP4 protein levels in comparison to the normal/overweight subjects (p<0.01). Serum-RBP4 levels were normalized in obese/diabetic subjects treated with diet or metformin (p<0.05). Adipose-tissue RBP4 protein levels were comparable between all three groups of subjects and so were serum- and adipose-transthyretin (TTR) levels. Adipose-tissue PTP1B mRNA levels were increased in obese subjects in comparison to normal/overweight subjects (p<0.05), however diet and/or metformin treatment did not reverse this effect. Adipose-tissue BIP, ATF4 and GRP94 expression levels were unchanged in obese and obese/diabetic subjects.
Conclusions: Human obesity results in an increase in serum, but not adipose-tissue, RBP4 protein levels and these are normalized in obese/diabetic subjects, which exhibit improvements in insulin sensitivity through diet or metformin treatment. However, whilst adipose-tissue PTP1B mRNA levels do increase in obese Scottish subjects, these remain high in obese/diabetics on diet or metformin treatment.