TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

Abstract Introduction Preclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is TAAR1 and 5-HT 1A agonist currently in Phase 3 clinical trials for treatment schizophrenia. Here we summarize preclinical results assessing effects ulotaront on weight parameters. Methods Effects administration were evaluated oral glucose tolerance (oGTT), gastric emptying, rodent models gain (high-fat diet [HFD]-, corticosterone-, olanzapine-induced). Results Following 15-day ulotaront, rats HFD showed dose-dependent reduction body weight, food intake, liver triglyceride content compared to controls. In addition, more rapid reversal olanzapine-induced intake was observed switched (vs. vehicle). Consistent with weight-lowering rats, chronic normalized corticosterone-induced mice. Assessment oGTT excursion response acute naive diabetic db/db also delayed emptying mice—a likely mechanism driving reductions excursions during oGTT. Whole-brain c-fos imaging ulotaront-treated mice revealed increased neuronal activity several brain regions associated regulation signals. Conclusions The data indicate that not only lacks liabilities typically antipsychotics but can reduce improve models. underlying mechanisms may include TAAR1-mediated peripheral homeostasis and/or direct modulation homeostatic hedonic neurocircuits regulating energy balance. beneficial suggest substantially improved risk-benefit profile established antipsychotics. Funding Sunovion Pharmaceuticals Inc. Otsuka Pharmaceutical Development & Commercialization,