Clozapine modifies the differentiation program of human adipocytes inducing browning

Area of Science:

• Metabolic research
• Pharmacology
• Cell biology

Background:

• Second-generation antipsychotic drugs (SGAs) are associated with significant weight gain and cardio-metabolic risks.
• Understanding the cellular mechanisms behind SGA-induced metabolic changes is crucial for developing effective interventions.

Purpose of the Study:

• To investigate the effect of clozapine on human adipocyte differentiation and browning.
• To explore the role of serotonin receptors in clozapine-induced adipocyte browning.
• To assess the metabolic function of clozapine-modified adipocytes.

Main Methods:

• Ex vivo differentiation of human adipocytes and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes.
• Gene expression analysis (UCP1, ELOVL3, CIDEA, CYC1, PGC1A, TBX1).
• Laser scanning cytometry for morphological analysis.
• Measurement of oxygen consumption and cellular responses to stimuli.

Main Results:

• Clozapine, unlike other SGAs, induced browning features in differentiating adipocytes, including UCP1 expression and smaller lipid droplets.
• Up to 40% of adipocytes exhibited beige-like characteristics.
• Clozapine-induced browning was partially mediated by serotonin (5HT) receptor antagonism and was diminished by exogenous 5HT.
• Clozapine-induced beige cells showed altered oxygen consumption but a reduced response to cAMP stimulus.

Conclusions:

• Clozapine uniquely induces a beige-like phenotype in human adipocytes, distinct from classical brown adipocytes.
• These findings suggest that clozapine-induced 'masked' beige adipocytes could be a therapeutic target for managing SGA-induced weight gain.
• Targeting these cells may offer a novel strategy for counteracting adverse metabolic effects of antipsychotic medications.