Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway

Abstract

Metabolic disturbance is commonly observed in schizophrenia patients, and the metabolic impacts of atypical antipsychotics such as olanzapine (OLA) have received much attention. Drug naive schizophrenia patients display metabolic abnormality to varying degrees, but how this shapes the metabolic responses to chronic OLA exposure is unknown. Using high-fat diet (HFD, 8 weeks) induced obesity, here we explored the metabolic outcome of chronic OLA exposure in conditions of pre-existing metabolic disturbance. OLA treatment (2 mg/kg) for 4 weeks led to markedly reduced body weight and adiposity in obese mice, concomitant with reduced adipose inflammation and hepatic steatosis. No significant change was observed on insulin sensitivity or energy expenditure after OLA exposure. Mechanistically, OLA restored autophagic clearance in the subcutaneous adipose tissue of obese mice, in line with its potentiation of lysosomal function in adipocytes. The metabolic phenotypes induced by OLA were partially reversed by chemical suppression of autolysosome. Together, these data uncover distinct metabolic effects of OLA in obesity involving the regulation of adipose tissue autophagy, and suggest a complicated link between OLA therapy and metabolic disturbance in schizophrenia.