Olanzapine Induces Adipogenesis and Glucose Uptake by Activating Glycolysis and Synergizing with the PI3K-AKT Pathway.

Background: Administration of olanzapine (OLA) is closely associated with obesity and glycolipid abnormalities in patients with schizophrenia (SCZ), although the exact molecular mecha- nisms remain elusive.

Objective: We conducted comprehensive animal and molecular experiments to elucidate the mecha- nisms underlying OLA-induced weight gain.

Methods: We investigated the mechanisms of OLA-induced adipogenesis and lipid storage by em- ploying a real-time ATP production rate assay, glucose uptake test, and reactive oxygen species (ROS) detection in 3T3-L1 cells and AMSCs. Rodent models were treated with OLA using various interven- tion durations, dietary patterns (normal diets/western diets), and drug doses. We assessed body weight, epididymal and liver fat levels, and metabolic markers in both male and female mice.

Results: OLA accelerates adipogenesis by directly activating glycolysis and its downstream PI3K sig- naling pathway in differentiated adipocytes. OLA promotes glucose uptake in differentiated 3T3-L1 preadipocytes. In mouse models with normal glycolipid metabolism, OLA administration failed to in- crease food intake and weight gain despite elevated GAPDH expression, a marker related to glycolysis and PI3K-AKT. This supports the notion that glycolysis plays a significant role in OLA-induced met- abolic dysfunction.

Conclusion: OLA induces glycolysis and activates the downstream PI3K-AKT signaling pathway, thereby promoting adipogenesis.