Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress

Autores: Korobkina, Ekaterina D.; Martinez Calejman, Camila; Haley, John A.; Kelly, Miranda E.; Li, Huawei; Gaughan, Maria; Chen, Qingbo; Pepper, Hannah L.; Ahmad, Hafsah; Boucher, Alexander; Fluharty, Shelagh M.; Lin, Te-Yueh; Lotun, Anoushka; Peura, Jessica; Trefely, Sophie; Green, Courtney R.; Vo, Paula; Semenkovich, Clay F.; Pitarresi, Jason R.; Spinelli, Jessica B.; Aydemir, Ozkan; Metallo, Christian M.; Lynes, Matthew D.; Jang, Cholsoon; Snyder, Nathaniel W.; Wellen, Kathryn E.; Guertin, David A.
Año de publicación: 2024
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.
Fil: Korobkina, Ekaterina D.. University Of Massachussets. Medical School; Estados Unidos
Fil: Martinez Calejman, Camila. University Of Massachussets. Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Haley, John A.. University Of Massachussets. Medical School; Estados Unidos
Fil: Kelly, Miranda E.. University of California at Irvine; Estados Unidos
Fil: Li, Huawei. University Of Massachussets. Medical School; Estados Unidos
Fil: Gaughan, Maria. University of Massachussets; Estados Unidos
Fil: Chen, Qingbo. University Of Massachussets. Medical School; Estados Unidos
Fil: Pepper, Hannah L.. University of Pennsylvania; Estados Unidos
Fil: Ahmad, Hafsah. University of Pennsylvania; Estados Unidos
Fil: Boucher, Alexander. University Of Massachussets. Medical School; Estados Unidos
Fil: Fluharty, Shelagh M.. University Of Massachussets. Medical School; Estados Unidos
Fil: Lin, Te-Yueh. University Of Massachussets. Medical School; Estados Unidos
Fil: Lotun, Anoushka. University Of Massachussets. Medical School; Estados Unidos
Fil: Peura, Jessica. University Of Massachussets. Medical School; Estados Unidos
Fil: Trefely, Sophie. University of Pennsylvania; Estados Unidos
Fil: Green, Courtney R.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados Unidos
Fil: Vo, Paula. University Of Massachussets. Medical School; Estados Unidos
Fil: Semenkovich, Clay F.. University Of Massachussets. Medical School; Estados Unidos
Fil: Pitarresi, Jason R.. University Of Massachussets. Medical School; Estados Unidos
Fil: Spinelli, Jessica B.. University Of Massachussets. Medical School; Estados Unidos
Fil: Aydemir, Ozkan. University Of Massachussets. Medical School; Estados Unidos
Fil: Metallo, Christian M.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados Unidos
Fil: Lynes, Matthew D.. Center For Clinical And Translational Research, Maine M; Estados Unidos
Fil: Jang, Cholsoon. University of California at Irvine; Estados Unidos
Fil: Snyder, Nathaniel W.. Temple University; Estados Unidos
Fil: Wellen, Kathryn E.. University of Pennsylvania; Estados Unidos
Fil: Guertin, David A.. University Of Massachussets. Medical School; Estados Unidos
Materia: Brown Fat
ATP citrate lyase
metabolism
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/275179

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spelling	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stressKorobkina, Ekaterina D.Martinez Calejman, CamilaHaley, John A.Kelly, Miranda E.Li, HuaweiGaughan, MariaChen, QingboPepper, Hannah L.Ahmad, HafsahBoucher, AlexanderFluharty, Shelagh M.Lin, Te-YuehLotun, AnoushkaPeura, JessicaTrefely, SophieGreen, Courtney R.Vo, PaulaSemenkovich, Clay F.Pitarresi, Jason R.Spinelli, Jessica B.Aydemir, OzkanMetallo, Christian M.Lynes, Matthew D.Jang, CholsoonSnyder, Nathaniel W.Wellen, Kathryn E.Guertin, David A.Brown FatATP citrate lyasemetabolismhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.Fil: Korobkina, Ekaterina D.. University Of Massachussets. Medical School; Estados UnidosFil: Martinez Calejman, Camila. University Of Massachussets. Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Haley, John A.. University Of Massachussets. Medical School; Estados UnidosFil: Kelly, Miranda E.. University of California at Irvine; Estados UnidosFil: Li, Huawei. University Of Massachussets. Medical School; Estados UnidosFil: Gaughan, Maria. University of Massachussets; Estados UnidosFil: Chen, Qingbo. University Of Massachussets. Medical School; Estados UnidosFil: Pepper, Hannah L.. University of Pennsylvania; Estados UnidosFil: Ahmad, Hafsah. University of Pennsylvania; Estados UnidosFil: Boucher, Alexander. University Of Massachussets. Medical School; Estados UnidosFil: Fluharty, Shelagh M.. University Of Massachussets. Medical School; Estados UnidosFil: Lin, Te-Yueh. University Of Massachussets. Medical School; Estados UnidosFil: Lotun, Anoushka. University Of Massachussets. Medical School; Estados UnidosFil: Peura, Jessica. University Of Massachussets. Medical School; Estados UnidosFil: Trefely, Sophie. University of Pennsylvania; Estados UnidosFil: Green, Courtney R.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados UnidosFil: Vo, Paula. University Of Massachussets. Medical School; Estados UnidosFil: Semenkovich, Clay F.. University Of Massachussets. Medical School; Estados UnidosFil: Pitarresi, Jason R.. University Of Massachussets. Medical School; Estados UnidosFil: Spinelli, Jessica B.. University Of Massachussets. Medical School; Estados UnidosFil: Aydemir, Ozkan. University Of Massachussets. Medical School; Estados UnidosFil: Metallo, Christian M.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados UnidosFil: Lynes, Matthew D.. Center For Clinical And Translational Research, Maine M; Estados UnidosFil: Jang, Cholsoon. University of California at Irvine; Estados UnidosFil: Snyder, Nathaniel W.. Temple University; Estados UnidosFil: Wellen, Kathryn E.. University of Pennsylvania; Estados UnidosFil: Guertin, David A.. University Of Massachussets. Medical School; Estados UnidosSpringer2024-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/275179Korobkina, Ekaterina D.; Martinez Calejman, Camila; Haley, John A.; Kelly, Miranda E.; Li, Huawei; et al.; Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress; Springer; Nature Metabolism; 6; 11; 10-2024; 2187-22022522-5812CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s42255-024-01143-3info:eu-repo/semantics/altIdentifier/doi/10.1038/s42255-024-01143-3info:eu-repo/semantics/altIdentifier/url/https://pmc.ncbi.nlm.nih.gov/articles/PMC11841677/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-03T08:43:54Zoai:ri.conicet.gov.ar:11336/275179instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-12-03 08:43:54.808CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
title	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
spellingShingle	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress Korobkina, Ekaterina D. Brown Fat ATP citrate lyase metabolism
title_short	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
title_full	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
title_fullStr	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
title_full_unstemmed	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
title_sort	Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress
dc.creator.none.fl_str_mv	Korobkina, Ekaterina D. Martinez Calejman, Camila Haley, John A. Kelly, Miranda E. Li, Huawei Gaughan, Maria Chen, Qingbo Pepper, Hannah L. Ahmad, Hafsah Boucher, Alexander Fluharty, Shelagh M. Lin, Te-Yueh Lotun, Anoushka Peura, Jessica Trefely, Sophie Green, Courtney R. Vo, Paula Semenkovich, Clay F. Pitarresi, Jason R. Spinelli, Jessica B. Aydemir, Ozkan Metallo, Christian M. Lynes, Matthew D. Jang, Cholsoon Snyder, Nathaniel W. Wellen, Kathryn E. Guertin, David A.
author	Korobkina, Ekaterina D.
author_facet	Korobkina, Ekaterina D. Martinez Calejman, Camila Haley, John A. Kelly, Miranda E. Li, Huawei Gaughan, Maria Chen, Qingbo Pepper, Hannah L. Ahmad, Hafsah Boucher, Alexander Fluharty, Shelagh M. Lin, Te-Yueh Lotun, Anoushka Peura, Jessica Trefely, Sophie Green, Courtney R. Vo, Paula Semenkovich, Clay F. Pitarresi, Jason R. Spinelli, Jessica B. Aydemir, Ozkan Metallo, Christian M. Lynes, Matthew D. Jang, Cholsoon Snyder, Nathaniel W. Wellen, Kathryn E. Guertin, David A.
author_role	author
author2	Martinez Calejman, Camila Haley, John A. Kelly, Miranda E. Li, Huawei Gaughan, Maria Chen, Qingbo Pepper, Hannah L. Ahmad, Hafsah Boucher, Alexander Fluharty, Shelagh M. Lin, Te-Yueh Lotun, Anoushka Peura, Jessica Trefely, Sophie Green, Courtney R. Vo, Paula Semenkovich, Clay F. Pitarresi, Jason R. Spinelli, Jessica B. Aydemir, Ozkan Metallo, Christian M. Lynes, Matthew D. Jang, Cholsoon Snyder, Nathaniel W. Wellen, Kathryn E. Guertin, David A.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Brown Fat ATP citrate lyase metabolism
topic	Brown Fat ATP citrate lyase metabolism
purl_subject.fl_str_mv	https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv	Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT. Fil: Korobkina, Ekaterina D.. University Of Massachussets. Medical School; Estados Unidos Fil: Martinez Calejman, Camila. University Of Massachussets. Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Haley, John A.. University Of Massachussets. Medical School; Estados Unidos Fil: Kelly, Miranda E.. University of California at Irvine; Estados Unidos Fil: Li, Huawei. University Of Massachussets. Medical School; Estados Unidos Fil: Gaughan, Maria. University of Massachussets; Estados Unidos Fil: Chen, Qingbo. University Of Massachussets. Medical School; Estados Unidos Fil: Pepper, Hannah L.. University of Pennsylvania; Estados Unidos Fil: Ahmad, Hafsah. University of Pennsylvania; Estados Unidos Fil: Boucher, Alexander. University Of Massachussets. Medical School; Estados Unidos Fil: Fluharty, Shelagh M.. University Of Massachussets. Medical School; Estados Unidos Fil: Lin, Te-Yueh. University Of Massachussets. Medical School; Estados Unidos Fil: Lotun, Anoushka. University Of Massachussets. Medical School; Estados Unidos Fil: Peura, Jessica. University Of Massachussets. Medical School; Estados Unidos Fil: Trefely, Sophie. University of Pennsylvania; Estados Unidos Fil: Green, Courtney R.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados Unidos Fil: Vo, Paula. University Of Massachussets. Medical School; Estados Unidos Fil: Semenkovich, Clay F.. University Of Massachussets. Medical School; Estados Unidos Fil: Pitarresi, Jason R.. University Of Massachussets. Medical School; Estados Unidos Fil: Spinelli, Jessica B.. University Of Massachussets. Medical School; Estados Unidos Fil: Aydemir, Ozkan. University Of Massachussets. Medical School; Estados Unidos Fil: Metallo, Christian M.. University Of California At San Diego. Skaggs School Of Pharmacy & Pharmaceutical Sciences.; Estados Unidos Fil: Lynes, Matthew D.. Center For Clinical And Translational Research, Maine M; Estados Unidos Fil: Jang, Cholsoon. University of California at Irvine; Estados Unidos Fil: Snyder, Nathaniel W.. Temple University; Estados Unidos Fil: Wellen, Kathryn E.. University of Pennsylvania; Estados Unidos Fil: Guertin, David A.. University Of Massachussets. Medical School; Estados Unidos
description	Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.
publishDate	2024
dc.date.none.fl_str_mv	2024-10
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/11336/275179 Korobkina, Ekaterina D.; Martinez Calejman, Camila; Haley, John A.; Kelly, Miranda E.; Li, Huawei; et al.; Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress; Springer; Nature Metabolism; 6; 11; 10-2024; 2187-2202 2522-5812 CONICET Digital CONICET
url	http://hdl.handle.net/11336/275179
identifier_str_mv	Korobkina, Ekaterina D.; Martinez Calejman, Camila; Haley, John A.; Kelly, Miranda E.; Li, Huawei; et al.; Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress; Springer; Nature Metabolism; 6; 11; 10-2024; 2187-2202 2522-5812 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s42255-024-01143-3 info:eu-repo/semantics/altIdentifier/doi/10.1038/s42255-024-01143-3 info:eu-repo/semantics/altIdentifier/url/https://pmc.ncbi.nlm.nih.gov/articles/PMC11841677/
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dc.publisher.none.fl_str_mv	Springer
publisher.none.fl_str_mv	Springer
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repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress

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