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2026

Nat Metab . 2026 Feb;8(2):327-349. doi: 10.1038/s42255-026-01453-8. Epub 2026 Feb 5.

Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion

Meltem Weger, Daniel Mauvoisin, 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 A Betts, Jonathan D Johnston, Fanny Durussel, Dmitri Firsov, Stephane Fournier, Olivier Müller, Benjamin L Schulz, Robert G Parton, Benjamin D Weger, Frédéric Gachon

Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. Nestlé Research, Société des Produits Nestlé, Lausanne, Switzerland. Nantes Université, CNRS, INSERM, l'institut du thorax, Nantes, France. Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences, Vienna Biocenter, Campus Vienna Biocenter, Vienna, Austria. Metabolomics Core Technology Platform, Center for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany. Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. Protein Analysis Facility, University of Lausanne, Lausanne, Switzerland. Centre for Nutrition, Exercise, and Metabolism, Department for Health, University of Bath, Bath, UK. Department of Diabetes, Endocrinology, Nutritional Metabolism, and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia. Section of Chronobiology, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Department of Cardiology, Lausanne University Hospital, Lausanne, Switzerland. Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Centre for Microscopy and Microanalysis, The University of Queensland, St Lucia, Queensland, Australia. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia Department of Biomedicine, Aarhus University, Aarhus, Denmark Steno Diabetes Center Aarhus, Aarhus, Denmark

Service type: Stock strains

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.