Non-Caloric Sweeteners combined with glucose affect hypothalamic glucose sensing-induced insulin secretion, food re-intake through neuronal cellular metabolism: An in vivo and in vitro approaches

1Changes in brain activity associated with deleterious metabolic effects of non-caloric sweeteners (NCS) have been demonstrated in humans, particularly when their intake is concomitant with that of glucose. Here, we have focused on hypothalamic glucose sensing in rats, detecting increases in circulating glucose levels and in turn triggering various physiological controls. The identification of sweet-taste receptors in the hypothalamus has suggested that they participate in glucosensing mechanism, but the existence of a dialogue between different pathways has never been studied. Here, we tested the acute effects of hypothalamic glucosensing combined with a NCS (sucralose or acesulfame potassium (aceK)), the latter binding only to sweet-taste receptors, without producing energy. Our working hypothesis was that the concomitance of two contradictory signals (energetic, sweet glucose vs. non-energetic, sweet NCS) could be responsible for deleterious physiological effects. After validation that sweet taste receptors and their signaling expressions were indeed present in the rat hypothalamus, insulin secretion induced by hypothalamic glucosensing (increased glucose level) in the presence of sucralose and aceK was examined. Insulin release was reduced compared to glucose alone, while the two NCS alone have no effect. Regarding the satiety-inducing effect of glucose, concomitant injection of each NCS with glucose produced the opposite effect to that observed with glucose alone, with food intake being increased, an effect also present with NCS injected alone. Using the GT1-7 hypothalamic cell line expressing sweet-taste receptors, we showed that the ATP concentration which normally increases with rising glucose levels was dose-dependently decreased in the presence of NCS, an effect which is inhibited in the presence of gurmarin, a specific inhibitor of sweet-taste receptors. The increase in ROS production in response to rising glucose levels was enhanced in the presence of NCS, an effect that was blocked in the presence of gurmarin. In both cases, NCS have an inhibitory effect on stimulated mitochondrial respiration. Taken together, these results suggest that NCS via sweet-taste receptors interfere with mitochondrial signaling and/or energy production during hypothalamic glucose sensing.