Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state

Abstract Second-generation antipsychotics are widely used in the treatment of all forms of psychoses, but they often produce undesirable side effects, among which are weight gain and other elements of metabolic syndrome. The mechanisms of these adverse effects are not known. The liver and adipose tissue are the principal candidate organs implicated in the development of antipsychotic-induced metabolic adverse effects. The present study investigated in the rat the effects on liver and white adipose tissue of a chronic treatment (46 days) with olanzapine 2 mg/kg or haloperidol 1 mg/kg, as compared with a control solution. In the liver, the expression of key genes involved in glucose transport and lipid metabolism and of regulatory transcription factors, as well as the TNFα gene, was not altered in response to either antipsychotic. Similarly, key genes involved in glucose transport and lipid metabolism were not changed in adipose tissue. However, the white adipose tissue was inflammatory in olanzapine-treated rats, with extensive macrophage infiltration and a significant increase in TNFα expression. In the plasma, TNFα and IL-1β concentrations were slightly elevated. Chronic olanzapine treatment therefore produces a low-grade inflammatory state, likely initiated in the adipose tissue. Such an inflammatory state is known to be associated with an increased risk of insulin-resistance and cardiovascular diseases. This antipsychotic-induced inflammatory syndrome may participate in the inflammatory syndrome often observed in patients with schizophrenia. The strong and rather selective effect of olanzapine on TNFα expression may open new therapeutic opportunities for the prevention of olanzapine-induced metabolic abnormalities.