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

Nigel Hoggard1, Abdelali Agouni2, Nimesh Mody2, Mirela Delibegovic21Rowett Institute of Nutrition and Health, 2Integrative Physiology, University of Aberdeen, Aberdeen, UKBackground: 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 northeast 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 (BMI > 30) controlling their diabetes either by diet or the antidiabetic drug metformin. We analyzed their serum and adipose tissue RBP4 protein levels as well as adipose tissue mRNA expression of PTP1B, binding immunoglobulin protein (BIP), activated transcription factor 4 (ATF4), and glucose-regulated protein 94 (GRP94) alongside other markers of adiposity (percentage body fat, leptin, cholesterol, triglycerides) and insulin resistance (oral glucose tolerance tests, insulin, homeostatic model assessment–insulin resistance, C-reactive protein, and 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 as were serum and adipose transthyretin 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, while adipose tissue PTP1B mRNA levels increase in obese Scottish subjects, these remain high in obese/diabetics on diet or metformin treatment.Keywords: obesity, diabetes, metformin, PTP1B, RBP4, TTR, ER stress, UPR, GRP94, BIP, ATF4, insulin resistance, glucose homeostasi