Quantification of changes in human islet G protein-coupled receptor mRNA expression in obesity.

Abstract

G protein-coupled receptors (GPCRs) play crucial roles in regulating islet function, with Gαs- and Gαq-coupled receptors being linked to the stimulation of insulin secretion. We have quantified the mRNA expression of 384 non-olfactory GPCRs in islets isolated from lean and obese organ donors to determine alterations in islet GPCR mRNA expression in obesity. RT-qPCR was used to quantify GPCR mRNAs relative to five reference genes (ACTB, GAPDH, PPIA, TBP, and TFRC) in human islets isolated from lean (BMI=22.6± 0.5) and obese (BMI=32.0± 0.8) donors. Overall, 197 and 256 GPCR mRNAs were detected above trace level in islets from lean and obese donors, respectively, with 191 GPCR mRNAs being common to the lean and obese groups. 40.9% (n= 157) and 27.1% (n= 104) of the mRNAs were expressed at trace level whilst 7.8% and 6.3% were absent in islets from lean and obese donors, respectively. Hundred and seventeen GPCR mRNAs were upregulated at least twofold in islets from obese donors, and there was >twofold downregulation of 21 GPCR mRNAs. Of particular interest, several receptors signalling via Gαs or Gαq showed significant mRNA upregulation in islets from obese donors (fold increase: PTH2R: 54.0 ± 14.6; MC2R: 34.3 ± 11.5; RXFP1: 8.5± 2.1; HTR2B: 6.0 ± 2.0; GPR110: 3.9± 1.2; PROKR2: 3.9± 0.7). Under conditions of obesity, human islets showed significant alterations in mRNAs encoding numerous GPCRs. The increased expression of Gαs- and Gαq-coupled receptors that have not previously been investigated in β-cells opens up possibilities of novel therapeutic candidates that may lead to the potentiation of insulin secretion and/or β-cell mass to regulate glucose homeostasis.