Macrophage-derived secretome is sufficient to confer olanzapine-mediated insulin resistance in human adipocytes

• Published in: Comprehensive Psychoneuroendocrinology (Online) Vol. 7; p. 100073
• Main Authors: Dipta, Priya, Sarsenbayeva, Assel, Shmuel, Miriam, Forno, Francesca, Eriksson, Jan W., Pereira, Maria J., Abalo, Xesús M., Wabitsch, Martin, Thaysen-Andersen, Morten, Tirosh, Boaz
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.08.2021; Elsevier
• Subjects: Adipocytes; Antipsychotics; Inflammation; Insulin resistance; Macrophages; Preclinical Study; Antipsychotics; Insulin resistance; Inflammation; Adipocytes; Macrophages
• ISSN: 2666-4976; 2666-4976
• DOI: 10.1016/j.cpnec.2021.100073

Olanzapine and Aripiprazole are widely used second-generation antipsychotic drugs. Olanzapine, more than Aripiprazole, leads to considerable metabolic side effects including obesity and diabetes. While the underlying mechanisms are not fully understood, these side effects are likely associated with mild inflammation in the metabolic organs. An in vitro model that accurately recapitulates the metabolic impact of olanzapine and aripiprazole should be useful to elucidate the underlying mechanisms. We established co-cultures of matured adipocytes derived from the human SGBS cell line and the THP-1 human monocytic cell-derived or primary macrophages to explore the effects of both drugs on the response to insulin. Olanzapine, but not aripiprazole induced insulin resistance in SGBS adipocytes only when co-cultured with THP-1 or primary macrophages, polarized either into M0, M1 or M2. Noteworthy, M2 macrophages induced olanzapine-dependent insulin resistance in the absence of induction of pro-inflammatory cytokines. Insulin resistance by olanzapine was stronger than induced by high concentration of pro-inflammatory cytokines even in combinations, suggesting the contribution of factors other than the classical inflammatory cytokines to promote insulin resistance in adipocytes by olanzapine. Macrophage/adipocyte co-cultures recapitulate the features of olanzapine-induced insulin resistance and implicate the existence of yet unknown factors in mediating this effect. •Olanzapine has no direct effect on insulin signalling in adipocytes.•Olanzapine compromises insulin signalling in adipocytes by affecting macrophage secretome.•Naïve, M1 and M2 macrophages are affected by Olanzapine.•The metabolic effects of Olanzapine are recapitulated in co-cultures of SGBS and THP-1 cell lines.•Unkown secreteable factors are presumed to be involved in debilitating insulin signaling by Olanzapine.