Objective: Diabetes is associated with abnormal regulation of appetite. Dopaminergic activation in food reward induces binge eating disorder (BED) and leads to increase in food intake. On the other hand, recent studies have demonstrated that stimulation of angiotensin II type 2 (AT2) receptor inhibits dopamine (DA) synthesis. In this study, we investigated the relationship between DA level and BED after fasting condition in diabetic mice and the inhibitory effect of AT2 receptor stimulation on BED and body weight.
Methods: Adult male type 2 diabetic mice, KKAy, at 10 weeks of age were treated with an intraperitoneal injection of AT2 receptor agonist, compound 21 (C21), at the dose of 10 μg/kg/day or saline for 2 weeks. DA level in the striatum was measured by microdialysis. Short-term spatial memory and activity were assessed by Y-maze test. After these tests, brain samples were obtained and the expressions of DA receptor D1 (DRD1), DA receptor D2 (DRD2) and DA transporter (DAT) in the substantia nigra were evaluated by immunohistochemical staining.
Results: Food and water intake and DA level in the striatum were significantly increased 48 hours after fasting compared with non-fasting mice. Administration with C21 significantly attenuated these increase without affecting systolic blood pressure. Treatment with C21 remarkably improved short-term cognitive function and increased explore activity. Moreover, C21 treatment did not affect fasting-induced weight loss, but significantly inhibited rebound weight gain after refeeding compared with vehicle-treated group. In KKAy, the expressions of DRD1, DRD2 and DAT in the substantia nigra were markedly decreased compared with wild-type (C57BL/6J strain) mice, whereas these reductions were improved by administration of C21. Interestingly, we demonstrated that fasting decreased DRD1 and DRD2 expression and increased DAT; however, administration of C21 inhibited these reductions of DRD1 and DRD2.
Conclusion: Activation of AT2 receptor could contribute to inhibition of BED and rebound weight gain with modulation of dopamine signaling. These results indicate that stimulation of AT2 receptor may be a new therapeutic approach to improve the eating disorder associated with dopamine resistance.