Leptin sensitizing effect of 1,3-butanediol and its potential mechanism

Abstract Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in t...

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Autores principales:	Masayo Isoda, Ken Ebihara, Nagisa Sawayama, Akiko Murakami, Chihiro Ebihara, Koji Shibuya, Akihito Takei, Shoko Takei, Tetsuji Wakabayashi, Daisuke Yamamuro, Manabu Takahashi, Shuichi Nagashima, Shun Ishibashi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/55954b893e2a47f5a8684596d223f7c8
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spelling	oai:doaj.org-article:55954b893e2a47f5a8684596d223f7c82021-12-02T18:03:05ZLeptin sensitizing effect of 1,3-butanediol and its potential mechanism10.1038/s41598-021-96460-y2045-2322https://doaj.org/article/55954b893e2a47f5a8684596d223f7c82021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96460-yhttps://doaj.org/toc/2045-2322Abstract Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.Masayo IsodaKen EbiharaNagisa SawayamaAkiko MurakamiChihiro EbiharaKoji ShibuyaAkihito TakeiShoko TakeiTetsuji WakabayashiDaisuke YamamuroManabu TakahashiShuichi NagashimaShun IshibashiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masayo Isoda Ken Ebihara Nagisa Sawayama Akiko Murakami Chihiro Ebihara Koji Shibuya Akihito Takei Shoko Takei Tetsuji Wakabayashi Daisuke Yamamuro Manabu Takahashi Shuichi Nagashima Shun Ishibashi Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
description	Abstract Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.
format	article
author	Masayo Isoda Ken Ebihara Nagisa Sawayama Akiko Murakami Chihiro Ebihara Koji Shibuya Akihito Takei Shoko Takei Tetsuji Wakabayashi Daisuke Yamamuro Manabu Takahashi Shuichi Nagashima Shun Ishibashi
author_facet	Masayo Isoda Ken Ebihara Nagisa Sawayama Akiko Murakami Chihiro Ebihara Koji Shibuya Akihito Takei Shoko Takei Tetsuji Wakabayashi Daisuke Yamamuro Manabu Takahashi Shuichi Nagashima Shun Ishibashi
author_sort	Masayo Isoda
title	Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
title_short	Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
title_full	Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
title_fullStr	Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
title_full_unstemmed	Leptin sensitizing effect of 1,3-butanediol and its potential mechanism
title_sort	leptin sensitizing effect of 1,3-butanediol and its potential mechanism
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/55954b893e2a47f5a8684596d223f7c8
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Leptin sensitizing effect of 1,3-butanediol and its potential mechanism

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