Abstract
Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.
| Original language | English |
|---|---|
| Pages (from-to) | 673-677 |
| Number of pages | 5 |
| Journal | Science |
| Volume | 386 |
| Issue number | 6722 |
| DOIs | |
| State | Published - Nov 8 2024 |
Bibliographical note
Publisher Copyright:Copyright © 2024 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
Funding
The authors would like to thank M. Burrows, L. Pécout, R. Méndez-Hernández, T. Borner, T. Acevedo, M. Tackenberg, and all other members of the Lazar, Hayes, and de Lartigue labs for their invaluable help and discussion. We would also like to thank C. Holman and the Rodent Metabolic Phenotyping Core for their help with CLAMS experiments as well as the Penn Diabetes Research Center and Institute for Diabetes, Obesity, and Metabolism (DK19525). Funding: This research was funded by NIH grants T32DK007314 and F32DK128984 (L.N.W.), NIH grant R01DK45586 (M.A.L.), NIH grant R01DK105155 (M.R.H.), NIH grants R01DK116004 and R01DK094871 (G.L.), NIH grant P30DK19525 (M.A.L.), the JPB Foundation (M.A.L.), and the Cox Medical Institute (M.A.L.). Author contributions: Conceptualization: L.N.W., G.L., M.R.H., and M.A.L. Methodology: L.N.W., A.M.A., C.E.G., G.L., M.R.H., and M.A.L. Investigation: L.N.W., L.C.M., M.M., A.M.A., C.E.G., A.J.A., B.M.K., and D.M.Z. Visualization: L.N.W., L.C.M., M.M., and A.J.A. Funding acquisition: L.N.W., G.L., M.R.H., and M.A.L. Project administration: L.N.W., G.L., M.R.H., and M.A.L. Supervision: G.L., M.R.H., and M.A.L. Writing – original draft: L.N.W. and M.A.L. Writing – review and editing: L.N.W., L.C.M., M.M., A.M.A., C.E.G., A.J.A., B.M.K., D.M.Z., G.L., M.R.H., and M.A.L. Competing interests: The authors declare the following competing interests: M.A.L. is on the advisory board and has received research funding unrelated to these studies from Pfizer, serves on the advisory board and is cofounder of Flare Therapeutics, and has consulted for Madrigal Pharmaceuticals. M.R.H. receives additional research funding from Boehringer Ingelheim, Novo Nordisk, Pfizer, Gila Therapeutics, and Eli Lilly & Co. that was not used in support of these studies. L.N.W., L.C.M., M.M., A.M.A., C.E.G., A.J.A., B.M.K., D.M.Z., and G.L. have no competing interests to declare. Data and materials availability: The GEO accession number for RNA sequencing data reported in this paper is GSE248462. All data will be made available upon request to L.N.W. and M.A.L. M.A.L. obtained the Nr1d1 floxed mice under a material transfer agreement with Genoway. M.A.L. obtained the Nr1d2 floxed mice under a material transfer agreement with the Centre Européen de Recherche en Biologie et Médecine. Nr1d1fl/fl and Nr1d2fl/fl mice are available by request to M.A.L. REV-ERBa nd b floxed mice are available from M.A.L. under a material transfer agreement (MTA) with the University of Pennsylvania, Philadelphia, PA, USA, contingent upon permission from the Institut Clinique de la Souris (ICS; Strasbourg, France) from whom the University of Pennsylvania received the REV-ERBb floxed mice under a separate MTA with this requirement. License information: Copyright © 2024 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/ science-licenses-journal-article-reuse The authors would like to thank M. Burrows, L. Pécout, R. Méndez-Hernández, T. Borner, T. Acevedo, M. Tackenberg, and all other members of the Lazar, Hayes, and de Lartigue labs for their invaluable help and discussion. We would also like to thank C. Holman and the Rodent Metabolic Phenotyping Core for their help with CLAMS experiments as well as the Penn Diabetes Research Center and Institute for Diabetes, Obesity, and Metabolism (DK19525). This research was funded by NIH grants T32DK007314 and F32DK128984 (L.N.W.), NIH grant R01DK45586 (M.A.L.), NIH grant R01DK105155 (M.R.H.), NIH grants R01DK116004 and R01DK094871 (G.L.), NIH grant P30DK19525 (M.A.L.), the JPB Foundation (M.A.L.), and the Cox Medical Institute (M.A.L.).
| Funders | Funder number |
|---|---|
| Cox Institute for Medical Research | |
| Diabetes Research Center, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania | |
| JPB Foundation | |
| Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania | |
| National Institutes of Health (NIH) | P30DK19525, R01DK116004, R01DK45586, R01DK094871, R01DK105155, F32DK128984, T32DK007314 |
| National Institutes of Health (NIH) |
ASJC Scopus subject areas
- General
