Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity

Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated...
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Autor*in:	Jae Woo Park [verfasserIn] Se Eun Park [verfasserIn] Wuhyun Koh [verfasserIn] Won Hee Jang [verfasserIn] Jong Han Choi [verfasserIn] Eun Roh [verfasserIn] Gil Myoung Kang [verfasserIn] Seong Jun Kim [verfasserIn] Hyo Sun Lim [verfasserIn] Chae Beom Park [verfasserIn] So Yeon Jeong [verfasserIn] Sang Yun Moon [verfasserIn] Chan Hee Lee [verfasserIn] Sang Yeob Kim [verfasserIn] Hyung Jin Choi [verfasserIn] Se Hee Min [verfasserIn] C. Justin Lee [verfasserIn] Min-Seon Kim [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Übergeordnetes Werk:	In: Nature Communications - Nature Portfolio, 2016, 15(2024), 1, Seite 15
Übergeordnetes Werk:	volume:15 ; year:2024 ; number:1 ; pages:15

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41467-024-46009-0

Katalog-ID:	DOAJ09230964X

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allfields	10.1038/s41467-024-46009-0 doi (DE-627)DOAJ09230964X (DE-599)DOAJ76bd7a81ac16438d856a226c7ca54b56 DE-627 ger DE-627 rakwb eng Jae Woo Park verfasserin aut Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity. Science Q Se Eun Park verfasserin aut Wuhyun Koh verfasserin aut Won Hee Jang verfasserin aut Jong Han Choi verfasserin aut Eun Roh verfasserin aut Gil Myoung Kang verfasserin aut Seong Jun Kim verfasserin aut Hyo Sun Lim verfasserin aut Chae Beom Park verfasserin aut So Yeon Jeong verfasserin aut Sang Yun Moon verfasserin aut Chan Hee Lee verfasserin aut Sang Yeob Kim verfasserin aut Hyung Jin Choi verfasserin aut Se Hee Min verfasserin aut C. Justin Lee verfasserin aut Min-Seon Kim verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 15 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:15 https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 kostenfrei https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 15
spelling	10.1038/s41467-024-46009-0 doi (DE-627)DOAJ09230964X (DE-599)DOAJ76bd7a81ac16438d856a226c7ca54b56 DE-627 ger DE-627 rakwb eng Jae Woo Park verfasserin aut Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity. Science Q Se Eun Park verfasserin aut Wuhyun Koh verfasserin aut Won Hee Jang verfasserin aut Jong Han Choi verfasserin aut Eun Roh verfasserin aut Gil Myoung Kang verfasserin aut Seong Jun Kim verfasserin aut Hyo Sun Lim verfasserin aut Chae Beom Park verfasserin aut So Yeon Jeong verfasserin aut Sang Yun Moon verfasserin aut Chan Hee Lee verfasserin aut Sang Yeob Kim verfasserin aut Hyung Jin Choi verfasserin aut Se Hee Min verfasserin aut C. Justin Lee verfasserin aut Min-Seon Kim verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 15 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:15 https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 kostenfrei https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 15
allfields_unstemmed	10.1038/s41467-024-46009-0 doi (DE-627)DOAJ09230964X (DE-599)DOAJ76bd7a81ac16438d856a226c7ca54b56 DE-627 ger DE-627 rakwb eng Jae Woo Park verfasserin aut Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity. Science Q Se Eun Park verfasserin aut Wuhyun Koh verfasserin aut Won Hee Jang verfasserin aut Jong Han Choi verfasserin aut Eun Roh verfasserin aut Gil Myoung Kang verfasserin aut Seong Jun Kim verfasserin aut Hyo Sun Lim verfasserin aut Chae Beom Park verfasserin aut So Yeon Jeong verfasserin aut Sang Yun Moon verfasserin aut Chan Hee Lee verfasserin aut Sang Yeob Kim verfasserin aut Hyung Jin Choi verfasserin aut Se Hee Min verfasserin aut C. Justin Lee verfasserin aut Min-Seon Kim verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 15 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:15 https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 kostenfrei https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 15
allfieldsGer	10.1038/s41467-024-46009-0 doi (DE-627)DOAJ09230964X (DE-599)DOAJ76bd7a81ac16438d856a226c7ca54b56 DE-627 ger DE-627 rakwb eng Jae Woo Park verfasserin aut Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity. Science Q Se Eun Park verfasserin aut Wuhyun Koh verfasserin aut Won Hee Jang verfasserin aut Jong Han Choi verfasserin aut Eun Roh verfasserin aut Gil Myoung Kang verfasserin aut Seong Jun Kim verfasserin aut Hyo Sun Lim verfasserin aut Chae Beom Park verfasserin aut So Yeon Jeong verfasserin aut Sang Yun Moon verfasserin aut Chan Hee Lee verfasserin aut Sang Yeob Kim verfasserin aut Hyung Jin Choi verfasserin aut Se Hee Min verfasserin aut C. Justin Lee verfasserin aut Min-Seon Kim verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 15 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:15 https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 kostenfrei https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 15
allfieldsSound	10.1038/s41467-024-46009-0 doi (DE-627)DOAJ09230964X (DE-599)DOAJ76bd7a81ac16438d856a226c7ca54b56 DE-627 ger DE-627 rakwb eng Jae Woo Park verfasserin aut Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity. Science Q Se Eun Park verfasserin aut Wuhyun Koh verfasserin aut Won Hee Jang verfasserin aut Jong Han Choi verfasserin aut Eun Roh verfasserin aut Gil Myoung Kang verfasserin aut Seong Jun Kim verfasserin aut Hyo Sun Lim verfasserin aut Chae Beom Park verfasserin aut So Yeon Jeong verfasserin aut Sang Yun Moon verfasserin aut Chan Hee Lee verfasserin aut Sang Yeob Kim verfasserin aut Hyung Jin Choi verfasserin aut Se Hee Min verfasserin aut C. Justin Lee verfasserin aut Min-Seon Kim verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 15 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:15 https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 kostenfrei https://doi.org/10.1038/s41467-024-46009-0 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 15
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author	Jae Woo Park
spellingShingle	Jae Woo Park misc Science misc Q Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
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topic_title	Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
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title	Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
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title_full	Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
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author_browse	Jae Woo Park Se Eun Park Wuhyun Koh Won Hee Jang Jong Han Choi Eun Roh Gil Myoung Kang Seong Jun Kim Hyo Sun Lim Chae Beom Park So Yeon Jeong Sang Yun Moon Chan Hee Lee Sang Yeob Kim Hyung Jin Choi Se Hee Min C. Justin Lee Min-Seon Kim
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title_sort	hypothalamic astrocyte nad+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
title_auth	Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
abstract	Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.
abstractGer	Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.
abstract_unstemmed	Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.
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title_short	Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
url	https://doi.org/10.1038/s41467-024-46009-0 https://doaj.org/article/76bd7a81ac16438d856a226c7ca54b56 https://doaj.org/toc/2041-1723
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author2	Se Eun Park Wuhyun Koh Won Hee Jang Jong Han Choi Eun Roh Gil Myoung Kang Seong Jun Kim Hyo Sun Lim Chae Beom Park So Yeon Jeong Sang Yun Moon Chan Hee Lee Sang Yeob Kim Hyung Jin Choi Se Hee Min C. Justin Lee Min-Seon Kim
author2Str	Se Eun Park Wuhyun Koh Won Hee Jang Jong Han Choi Eun Roh Gil Myoung Kang Seong Jun Kim Hyo Sun Lim Chae Beom Park So Yeon Jeong Sang Yun Moon Chan Hee Lee Sang Yeob Kim Hyung Jin Choi Se Hee Min C. Justin Lee Min-Seon Kim
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Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Science</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Q</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Se Eun Park</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Wuhyun Koh</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Won Hee Jang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jong Han Choi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eun Roh</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Gil Myoung Kang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Seong Jun Kim</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hyo Sun Lim</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chae Beom Park</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">So Yeon Jeong</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sang Yun Moon</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chan Hee Lee</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sang Yeob Kim</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hyung Jin Choi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Se Hee Min</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">C. 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Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity

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