Second Generation Antipsychotics Induce Metabolic Syndrome in Adipose Tissue Derived Mesenchymal Stem Cells Through aPKC-Dependent Pathway

Metabolic syndrome (MetS) defines a cluster of metabolic abnormalities that include obesity, and insulin resistance. Mature adipocytes and adipose derived stem cells (ADSC) of visceral white adipose tissue (vWAT) are primarily involved in the biological processes occurring during MetS, but the role of ADSCs has not been fully clarified yet. Patient undergoing long term treatment with second-generation antipsychotics (SGAs) are more prone to develop MetS with a high increase in comorbidities. In this study we investigated the effects of olanzapine and clozapine on primary human ADSCs, isolated from visceral WAT. Our evidence showed that these drugs impair the endolysosomal compartment with consequent accumulation of acidic vesicles and stimulation of lysosomal biogenesis through TFEB activation. Olanzapine disrupted insulin signaling by inhibiting insulin receptor endocytosis, turnover, and downstream pathways. Moreover, olanzapine impaired lipid droplets formation during adipogenic differentiation. Our data demonstrated that PKCζ is required for nuclear translocation of TFEB and acidic vesicles formation. Inhibition of PKCζ restored insulin receptor tyrosine phosphorylation, physiological turnover of insulin receptor, and downstream signaling upon olanzapine treatment. Lastly, we found that PKCζ activation induced by olanzapine is mediated by the intracellular increase of phosphatidic acid synthetized by PLD downstream GPCR signaling. In conclusion, our results show that treatment with SGAs affect endolysosomal compartment homeostasis and insulin signaling in a PKCζ-dependent manner. These evidence make SGAs an interesting class of compounds for studying the relationship between lysosomal pathways and metabolic dysfunctions, helping to further characterize the molecular alteration occurring in visceral adipose during MetS.