Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)‐induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs‐induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co‐treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ‐treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ‐induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ‐induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ‐induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs‐induced metabolic disturbances.

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Vitamin D Receptor Activation Attenuates Olanzapine‐Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress

Dang

Wang

Tang

et al. 2023

Advanced Biology

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Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: Effects on brown/beige adipose tissues and liver

Ferreira,

Folgueira,

Montes-San Lorenzo

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Metabolic effects of atypical antipsychotics: Molecular targets

Fonseca,

Carmo,

Martel

2023

J Neuroendocrinology

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Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits. Although the use of AAPs is associated with beneficial effects in these patients, they are also associated with undesired metabolic side effects, including metabolic syndrome (MetS). MeS is defined by the presence of metabolic abnormalities such as large waist circumference, dyslipidemia, fasting hyperglycemia and elevated blood pressure, which predispose to type 2 diabetes (T2D) and cardiovascular disease. In this review, the molecular and cellular mechanisms involved in these undesired metabolic abnormalities induced by AAPs will be described. These mechanisms are complex, as AAPs have multiple cellular targets, significantly affecting the activities of several hormones and neuromodulators. Additionally, AAPs affect all the relevant metabolic organs, namely the liver, pancreas, adipose tissue, skeletal muscle and intestine, and the central and peripheral nervous system as well. A better undertanding of the molecular targets linking AAPs with MetS and of the mechanisms responsible for clinically different side effects of distinct AAPs is needed. This knowledge will help in the development of novel AAPs with less adverse effects as well as of adjuvant therapies to patients receiving AAPs.This article is protected by copyright. All rights reserved.

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Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

Cited by 3 publications

References 150 publications

Vitamin D Receptor Activation Attenuates Olanzapine‐Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress

Vitamin D Receptor Activation Attenuates Olanzapine‐Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress

Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: Effects on brown/beige adipose tissues and liver

Metabolic effects of atypical antipsychotics: Molecular targets

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