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Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice

Olanzapine (OLZ), a widely used second-generation antipsychotic drug, is known to cause metabolic side effects, including diabetes and obesity. Interestingly, OLZ-induced metabolic side effects have been demonstrated to be more profound in females in human studies and animal models. Metformin (MET)...

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Autores principales: Suh, Sang Bum, Lee, Nayoung, Kim, Jaedeok, Kim, Saeha, Jang, Sooyeon, Park, Jong Kook, Lee, Keunwook, Choi, Soo Young, Kwon, Hyung-Joo, Lee, Chan Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596779/
https://www.ncbi.nlm.nih.gov/pubmed/36313357
http://dx.doi.org/10.3389/fphar.2022.906717
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author Suh, Sang Bum
Lee, Nayoung
Kim, Jaedeok
Kim, Saeha
Jang, Sooyeon
Park, Jong Kook
Lee, Keunwook
Choi, Soo Young
Kwon, Hyung-Joo
Lee, Chan Hee
author_facet Suh, Sang Bum
Lee, Nayoung
Kim, Jaedeok
Kim, Saeha
Jang, Sooyeon
Park, Jong Kook
Lee, Keunwook
Choi, Soo Young
Kwon, Hyung-Joo
Lee, Chan Hee
author_sort Suh, Sang Bum
collection PubMed
description Olanzapine (OLZ), a widely used second-generation antipsychotic drug, is known to cause metabolic side effects, including diabetes and obesity. Interestingly, OLZ-induced metabolic side effects have been demonstrated to be more profound in females in human studies and animal models. Metformin (MET) is often used as a medication for the metabolic side effects of OLZ. However, the mechanisms underlying OLZ-induced metabolic disturbances and their treatment remain unclear. Recent evidence has suggested that hypothalamic inflammation is a key component of the pathophysiology of metabolic disorders. On this background, we conducted this study with the following three objectives: 1) to investigate whether OLZ can independently induce hypothalamic microgliosis; 2) to examine whether there are sex-dependent differences in OLZ-induced hypothalamic microgliosis; and 3) to examine whether MET affects hypothalamic microgliosis. We found that administration of OLZ for 5 days induced systemic glucose intolerance and hypothalamic microgliosis and inflammation. Of note, both hypothalamic microglial activation and systemic glucose intolerance were far more evident in female mice than in male mice. The administration of MET attenuated hypothalamic microglial activation and prevented OLZ-induced systemic glucose intolerance and hypothalamic leptin resistance. Minocycline, a tetracycline derivative that prevents microgliosis, showed similar results when centrally injected. Our findings reveal that OLZ induces metabolic disorders by causing hypothalamic inflammation and that this inflammation is alleviated by MET administration.
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spelling pubmed-95967792022-10-27 Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice Suh, Sang Bum Lee, Nayoung Kim, Jaedeok Kim, Saeha Jang, Sooyeon Park, Jong Kook Lee, Keunwook Choi, Soo Young Kwon, Hyung-Joo Lee, Chan Hee Front Pharmacol Pharmacology Olanzapine (OLZ), a widely used second-generation antipsychotic drug, is known to cause metabolic side effects, including diabetes and obesity. Interestingly, OLZ-induced metabolic side effects have been demonstrated to be more profound in females in human studies and animal models. Metformin (MET) is often used as a medication for the metabolic side effects of OLZ. However, the mechanisms underlying OLZ-induced metabolic disturbances and their treatment remain unclear. Recent evidence has suggested that hypothalamic inflammation is a key component of the pathophysiology of metabolic disorders. On this background, we conducted this study with the following three objectives: 1) to investigate whether OLZ can independently induce hypothalamic microgliosis; 2) to examine whether there are sex-dependent differences in OLZ-induced hypothalamic microgliosis; and 3) to examine whether MET affects hypothalamic microgliosis. We found that administration of OLZ for 5 days induced systemic glucose intolerance and hypothalamic microgliosis and inflammation. Of note, both hypothalamic microglial activation and systemic glucose intolerance were far more evident in female mice than in male mice. The administration of MET attenuated hypothalamic microglial activation and prevented OLZ-induced systemic glucose intolerance and hypothalamic leptin resistance. Minocycline, a tetracycline derivative that prevents microgliosis, showed similar results when centrally injected. Our findings reveal that OLZ induces metabolic disorders by causing hypothalamic inflammation and that this inflammation is alleviated by MET administration. Frontiers Media S.A. 2022-10-12 /pmc/articles/PMC9596779/ /pubmed/36313357 http://dx.doi.org/10.3389/fphar.2022.906717 Text en Copyright © 2022 Suh, Lee, Kim, Kim, Jang, Park, Lee, Choi, Kwon and Lee. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Suh, Sang Bum
Lee, Nayoung
Kim, Jaedeok
Kim, Saeha
Jang, Sooyeon
Park, Jong Kook
Lee, Keunwook
Choi, Soo Young
Kwon, Hyung-Joo
Lee, Chan Hee
Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title_full Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title_fullStr Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title_full_unstemmed Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title_short Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
title_sort metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596779/
https://www.ncbi.nlm.nih.gov/pubmed/36313357
http://dx.doi.org/10.3389/fphar.2022.906717
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