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 journalArticlepeer-review

7 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 languageEnglish (US)
Article number112588
JournalCell reports
Volume42
Issue number6
DOIs
StatePublished - 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

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