Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction

Abstract

Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

Erchen Decoction regulates AMPK pathway in the treatment of metabolic syndrome induced by second-generation antipsychotics based on network pharmacology and molecular docking strategy

“…Clozapine activates AHR in the cytoplasm and inhibits AMPK signaling, which leads to increased lipid synthesis and metabolic disorders. [55,56]. The Glucocorticoid receptor gene NR3C1 rs6196 is significantly associated with weight gain in patients taking SGAs [57].…”

Plasma aryl hydrocarbon receptor associated with epicardial adipose tissue in men: a cross-sectional study

“…AhR plays an important role in adipocyte differentiation, and activation of AhR can significantly promote peroxisome proliferator-activated receptor γ (PPARγ) decay, which was shown to be involved in the mechanism of proteasome-dependent degradation in an in vitro study [ 44 ]. AhR activation induced not only adipogenesis but also vascular endothelial dysfunction in an in vivo model of male mice [ 45 ]. Distel et al [ 46 ] reported that PPARγ agonists could increase lipid turnover and decrease fatty acid release from EAT in an animal model of rats.…”

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

“…In the cytosol, AhR is bound by two heat shock protein 90 (HSP90) chaperones, molecules recently identified as both SCZ and Parkinson's disease (PD) targets [45][46][47][48][49][50][51][52]. Other AhR ligands significant for SCZ include DA, carbidopa, clozapine, melatonin, serotonin, microbial phenazines, and various pollutants, linking endogenous and exogenous molecules to this pathology [53][54][55][56].…”