Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms, a variety of animal models were used in experiments, but there is no reliable high-throughput screening method. Zebrafish is a common model organism for mental illness such as depression. In our research, we established chronic unpredictable mild stress (CUMS) models in C57BL/6 mice and zebrafish; the similarities in behavior and pathology suggest that zebrafish can replace rodents as high-throughput screening organisms. Stress mice (ip., 1 mg/kg/d, 3 days) and zebrafish (10 mg/L, 20 min) were treated with reserpine. As a result, reserpine caused depression-like behavior in mice, which was consistent with the results of the CUMS mice model. Additionally, reserpine reduced the locomotor ability and exploratory behavior of zebrafish, which was consistent with the results of the CUMS zebrafish model. Further analysis of the metabolic differences showed that the reserpine-induced zebrafish depression model was similar to the reserpine mice model and the CUMS mice model in the tyrosine metabolism pathway. The above results showed that the reserpine-induced depression zebrafish model was similar to the CUMS model from phenotype to internal metabolic changes and can replace the CUMS model for antidepressants screening. Moreover, the results from this model were obtained in a short time, which can shorten the cycle of drug screening and achieve high-throughput screening. Therefore, we believe it is a reliable high-throughput screening model.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, affecting up to 30% of the population, with approximately 20% of cases occurring in non-obese individuals. The recent shift to the term metabolic dysfunction-associated steatosis liver disease (MASLD) highlights the disease’s heterogeneity. However, there are no well-established animal models replicating non-obese NAFLD (NO-NAFLD). This study aimed to evaluate the relevance of the high-fat diet (HFD) combined with the propylthiouracil (PTU)-induced rat model in mimicking the histopathology and pathophysiology of NO-NAFLD. We first analyzed metabolic and clinical parameters between NO-NAFLD patients (Average BMI = 21.96 kg/m²) and obese NAFLD patients (Average BMI = 29.7 kg/m²). NO-NAFLD patients exhibited significantly higher levels of carnitines, phospholipids, and triglycerides. In the animal model, we examined serum lipid profiles, liver inflammation, histology, and transcriptomics. Hepatic steatosis in the HFD+PTU model at week 4 was comparable to that of the HFD model at week 8. The HFD+PTU model showed higher levels of carnitines, phospholipids, and triglycerides, supporting its relevance for NO-NAFLD. Additionally, the downregulation of lipid synthesis-related genes indicated differences in lipid accumulation between the two models. Overall, the HFD+PTU-induced rat model is a promising tool for studying the molecular mechanisms of NO-NAFLD.