Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion

Meltem Weger; Daniel  Mauvosin; Dominic  Hoyle; Jingkui  Wang; Eva  Martin; James  Rae; Charles  Ferguson; Glynis  Klinke; Michelle  Cielesh; Kyle L.  Macauslane; Mark Larance; Manfredo   Quadroni; Iain Templeman; Jean-Philippe Walhin; Leonidas G Karagounis; James Betts; Jonathan D. Johnston; Fanny Durussel; Dmitri  Firsov; Stephane  Fournier; Olivier  Müller; Benjamin L.  Schulz; Robert G.  Parton; Benjamin Weger; Frederic Gachon

doi:10.1038/s42255-026-01453-8

Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion

Meltem Weger
, Daniel Mauvosin
, Dominic Hoyle
, Jingkui Wang
, Eva Martin
, James Rae
, Charles Ferguson
, Glynis Klinke
, Michelle Cielesh
, Kyle L. Macauslane
, Mark Larance
, Manfredo Quadroni
, Iain Templeman
, Jean-Philippe Walhin
, Leonidas G Karagounis
, James Betts
, Jonathan D. Johnston
, Fanny Durussel
, Dmitri Firsov
, Stephane Fournier

Olivier Müller, Benjamin L. Schulz, Robert G. Parton, Benjamin Weger, Frederic Gachon

University of Queensland
Nestlé Research Centre
Universität Heidelberg
Ecole Polytechnique Fédérale de Lausanne
University of Sydney
University of Lausanne
University of Bern
Australian Catholic University
University of Surrey
Lausanne University Hospital
Aarhus University
Steno Diabetes Center Aarhus

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

3 Citations (SciVal)

Abstract

The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.

Original language	English
Pages (from-to)	327-349
Number of pages	23
Journal	Nature Metabolism
Volume	8
Issue number	2
Early online date	5 Feb 2026
DOIs	https://doi.org/10.1038/s42255-026-01453-8
Publication status	Published - Feb 2026

Data Availability Statement

All data presented in this study are available in the main article, Supplementary Information and Source data. The RNA-seq raw data generated for this publication have been deposited in the NCBI Gene Expression Omnibus (GEO) and are accessible through GEO accession numbers GSE283579 and GSE283707. Proteomics-associated data are available through ProteomeXchange with identifiers PXD037116 and PXD058564. Data from previously published studies used in this work are publicly available through the cited publications. Source data are provided with this paper.

Funding

This project has been supported by grants from the Australian National Health and Medical Research Council (Synergy grant 2019260 to F.G., Investigator grant 2016334 to B.D.W., Ideas grant 2030089 to M.L.), the National Institutes of Health (R01AG078241 to F.G.), the Novo Nordisk Foundation (Hallas-Møller Ascending Investigator grant 0087882 to F.G.), the Australian Research Council (Laureate Fellowship FL210100107 to R.G.P.), Alzheimer’s Association Research Fellowship (AARF-22-917584 to B.D.W.) and the University of Queensland.

Funders	Funder number
Centre Hospitalier Universitaire Vaudois
SydneyMS
University of Queensland
National Health and Medical Research Council	2030089, 2019260, 2016334
National Institutes of Health	R01AG078241
Australian Research Council	FL210100107
Alzheimer's Association	AARF-22-917584
Novo Nordisk Fonden	0087882

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s42255-026-01453-8Licence: CC BY

Cite this

Weger, M., Mauvosin, D., Hoyle, D., Wang, J., Martin, E., Rae, J., Ferguson, C., Klinke, G., Cielesh, M., Macauslane, K. L., Larance, M., Quadroni, M., Templeman, I., Walhin, J.-P., Karagounis, L. G., Betts, J., Johnston, J. D., Durussel, F., Firsov, D., ... Gachon, F. (2026). Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion. Nature Metabolism, 8(2), 327-349. https://doi.org/10.1038/s42255-026-01453-8

Weger, M, Mauvosin, D, Hoyle, D, Wang, J, Martin, E, Rae, J, Ferguson, C, Klinke, G, Cielesh, M, Macauslane, KL, Larance, M, Quadroni, M, Templeman, I, Walhin, J-P, Karagounis, LG, Betts, J, Johnston, JD, Durussel, F, Firsov, D, Fournier, S, Müller, O, Schulz, BL, Parton, RG, Weger, B & Gachon, F 2026, 'Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion', Nature Metabolism, vol. 8, no. 2, pp. 327-349. https://doi.org/10.1038/s42255-026-01453-8

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title = "Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion",

abstract = "The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion. ",

author = "Meltem Weger and Daniel Mauvosin and Dominic Hoyle and Jingkui Wang and Eva Martin and James Rae and Charles Ferguson and Glynis Klinke and Michelle Cielesh and Macauslane, \{Kyle L.\} and Mark Larance and Manfredo Quadroni and Iain Templeman and Jean-Philippe Walhin and Karagounis, \{Leonidas G\} and James Betts and Johnston, \{Jonathan D.\} and Fanny Durussel and Dmitri Firsov and Stephane Fournier and Olivier M{\"u}ller and Schulz, \{Benjamin L.\} and Parton, \{Robert G.\} and Benjamin Weger and Frederic Gachon",

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AU - Weger, Meltem

AU - Mauvosin, Daniel

AU - Hoyle, Dominic

AU - Wang, Jingkui

AU - Martin, Eva

AU - Rae, James

AU - Ferguson, Charles

AU - Klinke, Glynis

AU - Cielesh, Michelle

AU - Macauslane, Kyle L.

AU - Larance, Mark

AU - Quadroni, Manfredo

AU - Templeman, Iain

AU - Walhin, Jean-Philippe

AU - Karagounis, Leonidas G

AU - Betts, James

AU - Johnston, Jonathan D.

AU - Durussel, Fanny

AU - Firsov, Dmitri

AU - Fournier, Stephane

AU - Müller, Olivier

AU - Schulz, Benjamin L.

AU - Parton, Robert G.

AU - Weger, Benjamin

AU - Gachon, Frederic

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AB - The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.

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Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion

Abstract

Data Availability Statement

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UN SDGs

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