Liver and muscle circadian clocks cooperate to support glucose tolerance in mice

Jacob G. Smith; Kevin B. Koronowski; Thomas Mortimer; Tomoki Sato; Carolina M. Greco; Paul Petrus; Amandine Verlande; Siwei Chen; Muntaha Samad; Ekaterina Deyneka; Lavina Mathur; Ronnie Blazev; Jeffrey Molendijk; Arun Kumar; Oleg Deryagin; Mireia Vaca-Dempere; Valentina Sica; Peng Liu; Valerio Orlando; Benjamin L. Parker; Pierre Baldi; Patrick Simon Welz; Cholsoon Jang; Selma Masri; Salvador Aznar Benitah; Pura Muñoz-Cánoves; Paolo Sassone-Corsi

doi:10.1016/j.celrep.2023.112588

Liver and muscle circadian clocks cooperate to support glucose tolerance in mice

Jacob G. Smith^*, Kevin B. Koronowski^*, Thomas Mortimer, Tomoki Sato, Carolina M. Greco, Paul Petrus, Amandine Verlande, Siwei Chen, Muntaha Samad, Ekaterina Deyneka, Lavina Mathur, Ronnie Blazev, Jeffrey Molendijk, Arun Kumar, Oleg Deryagin, Mireia Vaca-Dempere, Valentina Sica, Peng Liu, Valerio Orlando, Benjamin L. ParkerPierre Baldi, Patrick Simon Welz, Cholsoon Jang, Selma Masri, Salvador Aznar Benitah^*, Pura Muñoz-Cánoves^*, Paolo Sassone-Corsi

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

Original language	English (US)
Article number	112588
Journal	Cell reports
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2023.112588
State	Published - Jun 27 2023

Bibliographical note

Funding Information:
This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine. K.B.K. was supported by NIH, NIDDK F32 Fellowship – DK121425. T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 749869. P.P. was funded by The Wenner-Gren Foundations, the Foundation Blanceflor Boncompagni Ludovisi, née Bildt and Tore Nilsson Foundation for Medical Science. V.S. was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 895390. A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C. M.S. and P.B. was in part supported by NIH grant GM123558. C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124. P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519, R01CA259370, and K22CA212045). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 787041), the Government of Cataluña (SGR grant), the Government of Spain (MINECO), the La Marató/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). P.M.-C. acknowledges funding from MICINN-RTI2018-096068, ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, DPP-Spain, Fundació La MaratóTV3- 80/19-202021, MWRF, and María-de-Maeztu Program for Units of Excellence to UPF (MDM-2014-0370), and the Severo-Ochoa Program for Centers of Excellence to CNIC (SEV2015-0505). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592, a Challenge Grant from the Novo Nordisk Foundation (NNF202585), KAUST funding (OSR-2019-CRG8-URF/1/4042), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01. Conceptualization, J.G.S. K.B.K. P.S.-C. V.O. P.L. P.B. P.-S.W. T.M. C.J. S.M. S.A.B. and P.M.-C.; formal analysis, S.C. M.S. E.D. L.M. O.D. C.J. J.G.S. and K.B.K.; funding acquisition, P.S.-C. V.O. S.M. S.A.B. and P.M.-C.; investigation, J.G.S. K.B.K. T.S. C.M.G. P.P. A.V. S.C. M.S. E.D. L.M. and V.S.; methodology, P.-S.W. S.M. J.G.S. and K.B.K.; project administration, S.M.; resources, P.-S.W. S.M. S.A.B. and P.M.-C.; supervision, S.M. S.A.B. P.M.-C. P.S.-C. P.B. V.O. B.L.P. and C.J.; visualization, J.G.S. K.B.K. S.C. M.S. E.D. and P.B.; writing – original draft, J.G.S. K.B.K. S.M. S.A.B. and P.M.-C.; writing – review & editing, J.G.S. K.B.K. R.B. J.M. A.V. P.L. T.M. A.K. M.V.-D. B.L.P. P.B. S.M. S.A.B. and P.M.-C. S.A.B. is a co-founder and scientific advisor of ONA Therapeutics. We support inclusive, diverse, and equitable conduct of research.

Funding Information:
This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine . K.B.K. was supported by NIH , NIDDK F32 Fellowship – DK121425 . T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 749869 . P.P. was funded by The Wenner-Gren Foundations , the Foundation Blanceflor Boncompagni Ludovisi, née Bildt and Tore Nilsson Foundation for Medical Science . V.S. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 895390 . A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C., M.S., and P.B. was in part supported by NIH grant GM123558 . C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124 . P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI / 10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519 , R01CA259370 , and K22CA212045 ). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 787041 ), the Government of Cataluña (SGR grant), the Government of Spain (MINECO), the La Marató/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505 ). P.M.-C. acknowledges funding from MICINN-RTI2018-096068 , ERC-2016-AdG-741966 , LaCaixa-HEALTH-HR17-00040 , MDA , UPGRADE-H2020-825825 , AFM, DPP-Spain , Fundació La MaratóTV3- 80/19-202021 , MWRF, and María-de-Maeztu Program for Units of Excellence to UPF ( MDM-2014-0370 ), and the Severo-Ochoa Program for Centers of Excellence to CNIC ( SEV2015-0505 ). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592 , a Challenge Grant from the Novo Nordisk Foundation ( NNF202585 ), KAUST funding ( OSR-2019-CRG8-URF/1/4042 ), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant ( CA-62203 ) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01 , 1S10OD010794-01 , and 1S10OD021718-01 .

Publisher Copyright:
© 2023 The Author(s)

Keywords

autonomy
Bmal1
circadian rhythms
CP: Metabolism
endocrinology
glucose
inter-organ crosstalk
liver
metabolism
muscle
systems biology

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2023.112588

Cite this

Smith, J. G., Koronowski, K. B., Mortimer, T., Sato, T., Greco, C. M., Petrus, P., Verlande, A., Chen, S., Samad, M., Deyneka, E., Mathur, L., Blazev, R., Molendijk, J., Kumar, A., Deryagin, O., Vaca-Dempere, M., Sica, V., Liu, P., Orlando, V., ... Sassone-Corsi, P. (2023). Liver and muscle circadian clocks cooperate to support glucose tolerance in mice. Cell reports, 42(6), Article 112588. https://doi.org/10.1016/j.celrep.2023.112588

@article{5f074ed77e3e45ad8405a5dab8785aea,

title = "Liver and muscle circadian clocks cooperate to support glucose tolerance in mice",

abstract = "Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.",

keywords = "autonomy, Bmal1, circadian rhythms, CP: Metabolism, endocrinology, glucose, inter-organ crosstalk, liver, metabolism, muscle, systems biology",

author = "Smith, {Jacob G.} and Koronowski, {Kevin B.} and Thomas Mortimer and Tomoki Sato and Greco, {Carolina M.} and Paul Petrus and Amandine Verlande and Siwei Chen and Muntaha Samad and Ekaterina Deyneka and Lavina Mathur and Ronnie Blazev and Jeffrey Molendijk and Arun Kumar and Oleg Deryagin and Mireia Vaca-Dempere and Valentina Sica and Peng Liu and Valerio Orlando and Parker, {Benjamin L.} and Pierre Baldi and Welz, {Patrick Simon} and Cholsoon Jang and Selma Masri and Benitah, {Salvador Aznar} and Pura Mu{\~n}oz-C{\'a}noves and Paolo Sassone-Corsi",

note = "Funding Information: This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine. K.B.K. was supported by NIH, NIDDK F32 Fellowship – DK121425. T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement 749869. P.P. was funded by The Wenner-Gren Foundations, the Foundation Blanceflor Boncompagni Ludovisi, n{\'e}e Bildt and Tore Nilsson Foundation for Medical Science. V.S. was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement 895390. A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C. M.S. and P.B. was in part supported by NIH grant GM123558. C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124. P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519, R01CA259370, and K22CA212045). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 787041), the Government of Catalu{\~n}a (SGR grant), the Government of Spain (MINECO), the La Marat{\'o}/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). P.M.-C. acknowledges funding from MICINN-RTI2018-096068, ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, DPP-Spain, Fundaci{\'o} La Marat{\'o}TV3- 80/19-202021, MWRF, and Mar{\'i}a-de-Maeztu Program for Units of Excellence to UPF (MDM-2014-0370), and the Severo-Ochoa Program for Centers of Excellence to CNIC (SEV2015-0505). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592, a Challenge Grant from the Novo Nordisk Foundation (NNF202585), KAUST funding (OSR-2019-CRG8-URF/1/4042), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01. Conceptualization, J.G.S. K.B.K. P.S.-C. V.O. P.L. P.B. P.-S.W. T.M. C.J. S.M. S.A.B. and P.M.-C.; formal analysis, S.C. M.S. E.D. L.M. O.D. C.J. J.G.S. and K.B.K.; funding acquisition, P.S.-C. V.O. S.M. S.A.B. and P.M.-C.; investigation, J.G.S. K.B.K. T.S. C.M.G. P.P. A.V. S.C. M.S. E.D. L.M. and V.S.; methodology, P.-S.W. S.M. J.G.S. and K.B.K.; project administration, S.M.; resources, P.-S.W. S.M. S.A.B. and P.M.-C.; supervision, S.M. S.A.B. P.M.-C. P.S.-C. P.B. V.O. B.L.P. and C.J.; visualization, J.G.S. K.B.K. S.C. M.S. E.D. and P.B.; writing – original draft, J.G.S. K.B.K. S.M. S.A.B. and P.M.-C.; writing – review & editing, J.G.S. K.B.K. R.B. J.M. A.V. P.L. T.M. A.K. M.V.-D. B.L.P. P.B. S.M. S.A.B. and P.M.-C. S.A.B. is a co-founder and scientific advisor of ONA Therapeutics. We support inclusive, diverse, and equitable conduct of research. Funding Information: This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine . K.B.K. was supported by NIH , NIDDK F32 Fellowship – DK121425 . T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement 749869 . P.P. was funded by The Wenner-Gren Foundations , the Foundation Blanceflor Boncompagni Ludovisi, n{\'e}e Bildt and Tore Nilsson Foundation for Medical Science . V.S. was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement 895390 . A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C., M.S., and P.B. was in part supported by NIH grant GM123558 . C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124 . P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI / 10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519 , R01CA259370 , and K22CA212045 ). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement 787041 ), the Government of Catalu{\~n}a (SGR grant), the Government of Spain (MINECO), the La Marat{\'o}/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505 ). P.M.-C. acknowledges funding from MICINN-RTI2018-096068 , ERC-2016-AdG-741966 , LaCaixa-HEALTH-HR17-00040 , MDA , UPGRADE-H2020-825825 , AFM, DPP-Spain , Fundaci{\'o} La Marat{\'o}TV3- 80/19-202021 , MWRF, and Mar{\'i}a-de-Maeztu Program for Units of Excellence to UPF ( MDM-2014-0370 ), and the Severo-Ochoa Program for Centers of Excellence to CNIC ( SEV2015-0505 ). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592 , a Challenge Grant from the Novo Nordisk Foundation ( NNF202585 ), KAUST funding ( OSR-2019-CRG8-URF/1/4042 ), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant ( CA-62203 ) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01 , 1S10OD010794-01 , and 1S10OD021718-01 . Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

day = "27",

doi = "10.1016/j.celrep.2023.112588",

language = "English (US)",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "6",

}

Smith, JG, Koronowski, KB, Mortimer, T, Sato, T, Greco, CM, Petrus, P, Verlande, A, Chen, S, Samad, M, Deyneka, E, Mathur, L, Blazev, R, Molendijk, J, Kumar, A, Deryagin, O, Vaca-Dempere, M, Sica, V, Liu, P , Orlando, V, Parker, BL, Baldi, P, Welz, PS, Jang, C, Masri, S, Benitah, SA, Muñoz-Cánoves, P & Sassone-Corsi, P 2023, 'Liver and muscle circadian clocks cooperate to support glucose tolerance in mice', Cell reports, vol. 42, no. 6, 112588. https://doi.org/10.1016/j.celrep.2023.112588

TY - JOUR

T1 - Liver and muscle circadian clocks cooperate to support glucose tolerance in mice

AU - Smith, Jacob G.

AU - Koronowski, Kevin B.

AU - Mortimer, Thomas

AU - Sato, Tomoki

AU - Greco, Carolina M.

AU - Petrus, Paul

AU - Verlande, Amandine

AU - Chen, Siwei

AU - Samad, Muntaha

AU - Deyneka, Ekaterina

AU - Mathur, Lavina

AU - Blazev, Ronnie

AU - Molendijk, Jeffrey

AU - Kumar, Arun

AU - Deryagin, Oleg

AU - Vaca-Dempere, Mireia

AU - Sica, Valentina

AU - Liu, Peng

AU - Orlando, Valerio

AU - Parker, Benjamin L.

AU - Baldi, Pierre

AU - Welz, Patrick Simon

AU - Jang, Cholsoon

AU - Masri, Selma

AU - Benitah, Salvador Aznar

AU - Muñoz-Cánoves, Pura

AU - Sassone-Corsi, Paolo

N1 - Funding Information: This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine. K.B.K. was supported by NIH, NIDDK F32 Fellowship – DK121425. T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 749869. P.P. was funded by The Wenner-Gren Foundations, the Foundation Blanceflor Boncompagni Ludovisi, née Bildt and Tore Nilsson Foundation for Medical Science. V.S. was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 895390. A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C. M.S. and P.B. was in part supported by NIH grant GM123558. C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124. P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519, R01CA259370, and K22CA212045). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 787041), the Government of Cataluña (SGR grant), the Government of Spain (MINECO), the La Marató/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). P.M.-C. acknowledges funding from MICINN-RTI2018-096068, ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, DPP-Spain, Fundació La MaratóTV3- 80/19-202021, MWRF, and María-de-Maeztu Program for Units of Excellence to UPF (MDM-2014-0370), and the Severo-Ochoa Program for Centers of Excellence to CNIC (SEV2015-0505). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592, a Challenge Grant from the Novo Nordisk Foundation (NNF202585), KAUST funding (OSR-2019-CRG8-URF/1/4042), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01. Conceptualization, J.G.S. K.B.K. P.S.-C. V.O. P.L. P.B. P.-S.W. T.M. C.J. S.M. S.A.B. and P.M.-C.; formal analysis, S.C. M.S. E.D. L.M. O.D. C.J. J.G.S. and K.B.K.; funding acquisition, P.S.-C. V.O. S.M. S.A.B. and P.M.-C.; investigation, J.G.S. K.B.K. T.S. C.M.G. P.P. A.V. S.C. M.S. E.D. L.M. and V.S.; methodology, P.-S.W. S.M. J.G.S. and K.B.K.; project administration, S.M.; resources, P.-S.W. S.M. S.A.B. and P.M.-C.; supervision, S.M. S.A.B. P.M.-C. P.S.-C. P.B. V.O. B.L.P. and C.J.; visualization, J.G.S. K.B.K. S.C. M.S. E.D. and P.B.; writing – original draft, J.G.S. K.B.K. S.M. S.A.B. and P.M.-C.; writing – review & editing, J.G.S. K.B.K. R.B. J.M. A.V. P.L. T.M. A.K. M.V.-D. B.L.P. P.B. S.M. S.A.B. and P.M.-C. S.A.B. is a co-founder and scientific advisor of ONA Therapeutics. We support inclusive, diverse, and equitable conduct of research. Funding Information: This paper is dedicated to Paolo Sassone-Corsi, a hugely inspiring scientist and mentor who remains an important influence on our work. We also thank P.S.C. Lab animal technician S. Sato and laboratory manager W. Orquiz for their valued contributions, as well as Aintzane Rueda and Alfonso Saera-Vila at Sequentia Biotech (Barcelona) for their work on RNA sequencing read alignment and differential gene expression analysis. J.G.S. was supported by Zymo-CEM Postdoctoral Fellowship (Zymo Research) awarded at the University of California, Irvine . K.B.K. was supported by NIH , NIDDK F32 Fellowship – DK121425 . T.S. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. C.M.G. was supported by the National Cancer Institute of the National Institutes of Health under award T32CA009054 and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 749869 . P.P. was funded by The Wenner-Gren Foundations , the Foundation Blanceflor Boncompagni Ludovisi, née Bildt and Tore Nilsson Foundation for Medical Science . V.S. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 895390 . A.V. was supported by the Hitachi-Nomura postdoctoral fellowship awarded through the Department of Biological Chemistry at the University of California, Irvine. The work of S.C., M.S., and P.B. was in part supported by NIH grant GM123558 . C.J. was supported by the AASLD Foundation Pinnacle Research Award in Liver Disease, the Edward Mallinckrodt, Jr. Foundation Award, and NIH/NIAAA R01 AA029124 . P.-S.W. is supported by grant RYC2019026661-I funded by MCIN/AEI / 10.13039/501100011033 and by “ESF Investing in your future.” Financial support for the S.M. laboratory is provided through the NIH/NCI (grants R01CA244519 , R01CA259370 , and K22CA212045 ). Research in the S.A.B. lab is supported partially by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 787041 ), the Government of Cataluña (SGR grant), the Government of Spain (MINECO), the La Marató/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC), and the Worldwide Cancer Research Foundation (WCRF). The IRB Barcelona is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505 ). P.M.-C. acknowledges funding from MICINN-RTI2018-096068 , ERC-2016-AdG-741966 , LaCaixa-HEALTH-HR17-00040 , MDA , UPGRADE-H2020-825825 , AFM, DPP-Spain , Fundació La MaratóTV3- 80/19-202021 , MWRF, and María-de-Maeztu Program for Units of Excellence to UPF ( MDM-2014-0370 ), and the Severo-Ochoa Program for Centers of Excellence to CNIC ( SEV2015-0505 ). Work in the P.S.-C. laboratory is supported by NIH grants R21DK114652 and R21AG053592 , a Challenge Grant from the Novo Nordisk Foundation ( NNF202585 ), KAUST funding ( OSR-2019-CRG8-URF/1/4042 ), and via access to the Genomics High Throughput Facility Shared Resource of the Cancer Center Support Grant ( CA-62203 ) and the UCI and NIH-shared instrumentation grants 1S10RR025496-01 , 1S10OD010794-01 , and 1S10OD021718-01 . Publisher Copyright: © 2023 The Author(s)

PY - 2023/6/27

Y1 - 2023/6/27

N2 - Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

AB - Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

KW - autonomy

KW - Bmal1

KW - circadian rhythms

KW - CP: Metabolism

KW - endocrinology

KW - glucose

KW - inter-organ crosstalk

KW - liver

KW - metabolism

KW - muscle

KW - systems biology

UR - http://www.scopus.com/inward/record.url?scp=85161061872&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112588

DO - 10.1016/j.celrep.2023.112588

M3 - Article

C2 - 37267101

AN - SCOPUS:85161061872

SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 6

M1 - 112588

ER -

Liver and muscle circadian clocks cooperate to support glucose tolerance in mice

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