Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway

Zhang, Xueli; Zhao, Yi; Liu, Yamin; Yang, Yuan; Shao, Hua; Zheng, Xiao

doi:10.1016/j.bcp.2018.10.001

Cited by 11 publications

(3 citation statements)

References 40 publications

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“…Indeed, while in ziprasidone and risperidone-treated cells the difference in LC3-II levels was similar to the control, indicating a normal autophagic flux, it was significantly reduced in U18666A- and olanzapine-treated cells (Fig. 3G ), indicating a reduction in autophagosome degradation [ 79 , 80 ], rather than an increase in the autophagic flux, as other publications indicated for olanzapine [ 81 , 82 ]. Similar results were previously obtained with haloperidol and clozapine, two antipsychotics known to block the autophagic flux [ 83 ].…”

Section: Resultssupporting

confidence: 53%

“…The relationship between autophagy and antipsychotics is not entirely clear and sometimes results are contradictory, depending on the cells lines used and on the assay performed to analyse the process. Olanzapine is reported to both induce and inhibit autophagy: it induces accumulation of autophagosomes and lysosomes and inhibits mitophagy in neuronal cells [ 90 ], and lysosomal membrane damage in rat hepatocytes [ 91 ], but it is also reported to induce autophagy with increased autophagosome formation in glioma cells, SHSY-5Y neuron-like cells and in pre-adypocytes [ 81 , 82 , 88 ]. We analysed autophagy in olanzapine-treated cells by using two different autophagic flux assays, obtaining similar results.…”

Section: Discussionmentioning

confidence: 99%

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Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients

Pozzi,

Vantaggiato,

Brivio

et al. 2024

Transl Psychiatry

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The metabolic effects induced by antipsychotics in vitro depend on their action on the trafficking and biosynthesis of sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar alterations in vitro, suggesting the low clinical usefulness of cellular studies. Moreover, the inhibition of peripheral AMPK was suggested as potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsychotics. We thus assessed, in clinically-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone, antipsychotics with respectively high, medium, low metabolic risk in patients, finding relevant differences among them. We highlighted that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intracellular lipids and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intracellular lipids; risperidone increases lipid accumulation, while it does not affect lysosomal function. These in vitro differences align with their different impact on patients. We also provided evidence that metformin add-on improved autophagy in olanzapine-treated cells and reduced lipid accumulation induced by both risperidone and olanzapine in an AMPK-dependent way; metformin also increased the production of bile acids to eliminate cholesterol accumulations caused by olanzapine. These results have different clinical implications. We demonstrated that antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the possibility of a personalised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by risperidone but not the one caused by olanzapine, that still activates SREBP2.

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Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients

Pozzi,

Vantaggiato,

Brivio

et al. 2024

Transl Psychiatry

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“…30 Chronic inflammation caused by ATM infiltration and M1 polarization play an important role in promoting olanzapineinduced insulin resistance. 31,32 In our study, olanzapine treatment at a dose of 3 mg/kg, which is close to human therapeutic dose, markedly increased monocyte migration and ATM infiltration in mouse sWAT.…”

Section: Amelioration Of Olanzapine-induced Monocyte Migration Into S...supporting

confidence: 67%

Gamma‐aminobutyric acid supplementation improves olanzapine‐induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue

Ren,

Xuan,

et al. 2024

Diabetes Obesity Metabolism

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AimsTo investigate whether gamma‐aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms.Materials and MethodsInsulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration.ResultsWe found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine‐induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine‐induced adipose tissue macrophage infiltration and M1‐like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine‐induced insulin resistance at least in part through a GABAB receptor‐dependent pathway.ConclusionsThese findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine‐induced metabolic disorders.

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HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor

Zuo,

Zhang,

Guo

et al. 2023

CURR MED SCI

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Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway

Cited by 11 publications

References 40 publications

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients

Gamma‐aminobutyric acid supplementation improves olanzapine‐induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor

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