Modulation of olfactory sensitivity and glucose-sensing by the feeding state in obese Zucker rats

The Zucker fa/fa rat has been widely used as an animal model to study obesity, since it recapitulates most of its behavioral and metabolic dysfunctions, such as hyperphagia, hyperglycemia and insulin resistance. Although it is well established that olfaction is under nutritional and hormonal influences, little is known about the impact of metabolic dysfunctions on olfactory performances and glucose-sensing in the olfactory system of the obese Zucker rat. In the present study, using a behavioral paradigm based on a conditioned olfactory aversion, we have shown that both obese and lean Zucker rats have a better olfactory sensitivity when they are fasted than when they are satiated. Interestingly, the obese Zucker rats displayed a higher olfactory sensitivity than their lean controls. By investigating the molecular mechanisms involved in glucose-sensing in the olfactory system, we demonstrated that sodium-coupled glucose transporters 1 (SGLT1) and insulin dependent glucose transporters 4 (GLUT4) are both expressed in the olfactory bulb (OB). By comparing the expression of GLUT4 and SGLT1 in OB of obese and lean Zucker rats, we found that only SGLT1 is regulated in genotype-dependent manner. Next, we used glucose oxidase biosensors to simultaneously measure in vivo the extracellular fluid glucose concentrations ([Gluc]ECF) in the OB and the cortex. Under metabolic steady state, we have determined that the OB contained twice the amount of glucose found in the cortex. In both regions, the [Gluc]ECF was 2 fold higher in obese rats compared to their lean controls. Under induced dynamic glycemia conditions, insulin injection produced a greater decrease of [Gluc]ECF in the OB than in the cortex. Glucose injection did not affect OB [Gluc]ECF in Zucker fa/fa rats. In conclusion, these results emphasize the importance of glucose for the OB network function and provide strong arguments towards establishing the OB glucose-sensing as a key factor for sensory olfactory processing.