Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle

Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, main...

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Autores principales:	Chongye Fang, Shuhei Hayashi, Xiaocui Du, Xianbin Cai, Bin Deng, Hongmei Zheng, Satoshi Ishido, Hiroko Tsutsui, Jun Sheng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd370
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spelling	oai:doaj.org-article:5b4f3709787b4fb0ba7fd5b3e7edd3702021-12-02T14:23:04ZCaffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle10.1038/s41598-021-86659-42045-2322https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd3702021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86659-4https://doaj.org/toc/2045-2322Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.Chongye FangShuhei HayashiXiaocui DuXianbin CaiBin DengHongmei ZhengSatoshi IshidoHiroko TsutsuiJun ShengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chongye Fang Shuhei Hayashi Xiaocui Du Xianbin Cai Bin Deng Hongmei Zheng Satoshi Ishido Hiroko Tsutsui Jun Sheng Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
description	Abstract Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.
format	article
author	Chongye Fang Shuhei Hayashi Xiaocui Du Xianbin Cai Bin Deng Hongmei Zheng Satoshi Ishido Hiroko Tsutsui Jun Sheng
author_facet	Chongye Fang Shuhei Hayashi Xiaocui Du Xianbin Cai Bin Deng Hongmei Zheng Satoshi Ishido Hiroko Tsutsui Jun Sheng
author_sort	Chongye Fang
title	Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_short	Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_full	Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_fullStr	Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_full_unstemmed	Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle
title_sort	caffeine protects against stress-induced murine depression through activation of pparγc1α-mediated restoration of the kynurenine pathway in the skeletal muscle
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5b4f3709787b4fb0ba7fd5b3e7edd370
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Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle

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