Metabolic diseases (type 2 diabetes (T2D) and obesity) prevalence is increasing in the world. This is partly related to a change in lifestyle with an increase of caloric intake and a decrease of physical activity. Environmental causes are also involved among them exposure to bisphenol A (BPA). The mode of action of the latter is unknown. Beyond a suggesting effect relayed by nuclear receptors, we propose that BPA can act by modulating the functionality of G protein-coupled receptors involved in the pathophysiology of metabolic disorders. In order to test this hypothesis, we analyzed the effect of BPA on the activity of MC4R and fatty acid receptor FFAR1 (GPR40). MC4R is involved in obesity by regulating dietary intake and energy balance. There are two ligands of MC4R: αMSH (agonist) and AgRP (inverse agonist). FFAR1 increases the glucose-dependent insulin secretion. It is a new therapeutic target in T2D.
Each receptor is transiently expressed in HEK293, and its activity is assessed by measuring cyclic AMP (cAMP) for MC4R, using a biosensor kit, or calcium for FFAR1, using a fluorimetric calcium sensor.
At a concentration of 10 nM, BPA increased by up to 30% the cAMP production induced by αMSH and reduced by half the inhibition induced by AgRP, without modifying the basal activity. These effects are specific for MC4R as BPA did not change the activity of the downstream effectors of cAMP pathway (adenylate cyclase, G protein or phosphodiesterases) or one of endogenous adenosine receptor (negative control).
In addition, 10 pM BPA decreased by one-third the calcium mobilization stimulated by GW9508 (a synthetic agonist of FFAR1).
We show here new effects of BPA with a disruption of G protein-coupled receptors activity, which may be worth to take into account when addressing the question of the link between endocrine disruptor and metabolic diseases.
20 - 23 May 2017
European Society of Endocrinology