Exploring the therapeutic potential of chlorogenic acid in alleviating olanzapine-induced metabolic syndrome in rats: a key role of hypothalamic satiety proteins

Objectives: Olanzapine (Olz) is an effective antipsychotic medication for schizophrenia; however, its use is associated with weight gain and metabolic disorders. Chlorogenic acid (CGA), a dietary polyphenol, has a promising potential for the treatment of obesity, diabetes, and hypertension. This study aimed to determine whether CGA could effectively manage Olz-induced metabolic syndrome (MetS) in a rat model, with metformin (Met) as a positive control.Methods: Female Wistar rats were divided into seven groups: control; Olz (5 mg/kg/day, IP); CGA (20, 40, and 80 mg/kg/day, gavage) plus Olz; Met (100 mg/kg/day, gavage) plus Olz; and CGA (80 mg/kg/day, gavage) for 30 days. Metabolic parameters including body weight, fasting blood glucose, triglycerides, and blood pressure were assessed. This study focused on evaluating serum levels of leptin and adiponectin, as well as hypothalamic protein expression of pro-opiomelanocortin (POMC), neuropeptide Y (NPY), AMP-activated protein kinase (AMPK), and 5-HT2C receptors (5-HT2CR), which are known to influence energy balance and potentially play a role in Olz-induced metabolic abnormalities.Results: Olz caused substantial hyperphagia, weight gain, hypertension, and liver damage, along with elevated fasting blood glucose, triglycerides, and leptin levels. CGA and Met mitigated these effects, although Olz-induced elevation of adiponectin levels remained unaffected by either treatment. Mechanistically, Olz reduced 5-HT2CR protein levels, a trend that was observed in the CGA and Met therapy groups. Olz also enhanced NPY protein levels and the pAMPK/AMPK ratio while lowering POMC protein levels. These alterations were reversed in rats administered CGA or Met.Discussion: These findings suggest that CGA effectively attenuated the adverse metabolic consequences of Olz by modulating leptin, NPY, POMC, and AMPK protein levels. CGA's therapeutic potential highlights its potential as a dietary intervention for managing antipsychotic-induced metabolic disturbances.