A Novel Synthetic Interfering Peptide Tat-3L4F Attenuates Olanzapine-Induced Weight Gain Through Disrupting Crosstalk Between Serotonin Receptor 2C and Protein Phosphatase and Tensin Homolog in Rats

Accompanied with profound efficacy, atypical antipsychotics (AAPs) contribute to metabolic adverse effects with few effective strategies to attenuate. Serotonin 5-HT2C receptor (HTR2C) plays a critical role in hyperphagia and weight gain induced by AAPs, and expression of phosphatase tensin homolog (PTEN) in the hypothalamus also affects feeding behavior and weight change. Moreover, PTEN has a physical crosstalk between PTEN and a region in the third intracellular loop (3L4F) of the HTR2C. Tat-3L4F has the property to disrupt crosstalk between PTEN and HTR2C. This is the first study to our knowledge to investigate the effect of Tat-3L4F on olanzapine-induced metabolic abnormalities and PTEN/ phosphatidylinositol 3-kinase/protein kinase B expression in the hypothalamus in rats.

Our present results reveal that Tat-3L4F is a potential pharmacological strategy for suppressing hyperphagia and weight gain induced by olanzapine, which acts through disrupting crosstalk between HTR2C and PTEN as a result of PTEN downregulation in the hypothalamus.

The effects of Tat-3L4F were investigated through measuring body weight, food intake, and blood glucose. In addition, PTEN/phosphatidylinositol 3-kinase/protein kinase B level in the hypothalamus was detected by immunofluorescence assay and western blot. Metabolites in the liver tissue were detected by liquid chromatography-mass spectrometry and analyzed by multivariate analyses and pairwise comparison.

Our results showed that hyperphagia and weight gain were evident in the olanzapine alone-fed rats but was attenuated after Tat-3L4F treatment. In addition, oral glucose tolerance test indicated blood glucose at 120 minutes was higher in the olanzapine alone-treated group than in groups treated with vehicle and olanzapine + Tat-3L4F (10 μmol kg-1 per day). Furthermore, compared with olanzapine alone treatment, treatment with Tat-3L4F (10 μmol kg-1 per day) significantly inhibited PTEN expression in the hypothalamus. The olanzapine alone-treated group had the highest bile acid level, followed by the olanzapine with Tat-3L4F (1 μmol kg-1) group, olanzapine with Tat-3L4F (10 μmol kg-1) group, and vehicle group. Conclusions: Our present results reveal that Tat-3L4F is a potential pharmacological strategy for suppressing hyperphagia and weight gain induced by olanzapine, which acts through disrupting crosstalk between HTR2C and PTEN as a result of PTEN downregulation in the hypothalamus.