Adropin expression reflects circadian, lipoprotein, and mitochondrial processes in human tissues

Adropin expression reflects circadian, lipoprotein, and mitochondrial processes in human tissues

The clinical significance of interindividual variation in circulating adropin levels is unclear. To better understand adropin biology at the whole-body level, we surveyed transcriptional structures co-regulated with the Energy Homeostasis Associated (ENHO) gene encoding adropin across human tissues...

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Main Authors: Joseph R. Stevens, Clemence Girardet, Mingqi Zhou, Farah Gamie, Geetika Aggarwal, Ryan P. McMillan, Matthew W. Hulver, Laurent O. Martinez, Marcel van der Brug, Bruno Vellas, Andrew D. Nguyen, Marcus M. Seldin, Andrew A. Butler, MAPT Study Group, Principal investigator, Coordination, Sophie Guyonnet, Project leader, Isabelle Carrié, CRA, Lauréane Brigitte, Investigators, Catherine Faisant, Françoise Lala, Julien Delrieu, Hélène Villars, Psychologists, Emeline Combrouze, Carole Badufle, Audrey Zueras, Methodology, statistical analysis and data management, Sandrine Andrieu, Christelle Cantet, Christophe Morin, Multidomain group, Gabor Abellan Van Kan, Charlotte Dupuy, Yves Rolland, Céline Caillaud, Pierre-Jean Ousset, Co-Investigators in associated centres, Jean-François Dartigues, Isabelle Marcet, Fleur Delva, Alexandra Foubert, Sandrine Cerda, Marie-Noëlle Cuffi, Corinne Costes, Olivier Rouaud, Patrick Manckoundia, Valérie Quipourt, Sophie Marilier, Evelyne Franon, Lawrence Bories, Marie-Laure Pader, Marie-France Basset, Bruno Lapoujade, Valérie Faure, Michael Li Yung Tong, Christine Malick-Loiseau, Evelyne Cazaban-Campistron, Françoise Desclaux, Colette Blatge, Thierry Dantoine, Cécile Laubarie-Mouret, Isabelle Saulnier, Jean-Pierre Clément, Marie-Agnès Picat, Laurence Bernard-Bourzeix, Stéphanie Willebois, Iléana Désormais, Noëlle Cardinaud, Marc Bonnefoy, Pierre Livet, Pascale Rebaudet, Claire Gédéon, Catherine Burdet, Flavien Terracol, Alain Pesce, Stéphanie Roth, Sylvie Chaillou, Sandrine Louchart, Kristel Sudres, Nicolas Lebrun, Nadège Barro-Belaygues, Jacques Touchon, Karim Bennys, Audrey Gabelle, Aurélia Romano, Lynda Touati, Cécilia Marelli, Cécile Pays, Philippe Robert, Franck Le Duff, Claire Gervais, Sébastien Gonfrier, Yannick Gasnier, Serge Bordes, Danièle Begorre, Christian Carpuat, Khaled Khales, Jean-François Lefebvre, Samira Misbah El Idrissi, Pierre Skolil, Jean-Pierre Salles, MRI group, Carole Dufouil, Stéphane Lehéricy, Marie Chupin, Jean-François Mangin, Ali Bouhayia, Michèle Allard, Frédéric Ricolfi, Dominique Dubois, Marie Paule Bonceour Martel, François Cotton, Alain Bonafé, Stéphane Chanalet, Françoise Hugon, Fabrice Bonneville, Christophe Cognard, François Chollet, PET scans group, Pierre Payoux, Thierry Voisin, Sophie Peiffer, Anne Hitzel, Michel Zanca, Jacques Monteil, Jacques Darcourt, Medico-economics group, Laurent Molinier, Hélène Derumeaux, Nadège Costa, Biological sample collection, Bertrand Perret, Claire Vinel, Sylvie Caspar-Bauguil, Safety management, Pascale Olivier-Abbal, IHU Open Science Group, Nicola Coley
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Molecular Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877825001036
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Summary:The clinical significance of interindividual variation in circulating adropin levels is unclear. To better understand adropin biology at the whole-body level, we surveyed transcriptional structures co-regulated with the Energy Homeostasis Associated (ENHO) gene encoding adropin across human tissues using Gene-Derived Correlations Across Tissues (GD-CAT). ENHO/adropin-related transcriptional structures with >1000 genes meeting the selection threshold (q < 0.001) occurred in 11/20 tissues. While most reflect local relationships, liver ENHO/adropin-related structures are dominated by transcripts expressed across metabolic tissues (skeletal muscle, adipose tissues, thyroid). Relationships between liver ENHO/adropin expression and skeletal muscle mitochondrial function were corroborated using liver-specific knockout mice. Within-liver ENHO/adropin transcriptional structures reflect lipoprotein metabolism (e.g., APOC1, p = 4.91 x 10−11; APOA1, p = 8.03 x 10−9), confirmed by correlations between plasma concentrations of adropin and indices of lipoprotein metabolism in MAPT samples. Moreover, statin treatment which increases hepatic cholesterol efflux, reduces plasma adropin levels. The ENHO gene contains retinoic acid receptor-related orphan receptor response elements (RORE), suggesting circadian control. Pan-organ transcriptional structures with liver ENHO/adropin or RORC overlap, reflecting the liver clock. Strong, local relationships between ENHO/adropin and circadian genes were also observed in most non-hepatic tissues. ENHO/adropin expression widely reflects activation of oxidative metabolic pathways and suppression of ribosomal functions and cell division. Finally, hippocampal ENHO/adropin expression correlates strongly with Alzheimer's disease risk genes identified by GWAS. In summary, activation of ENHO/adropin expression reflects cellular circadian and mitochondrial oxidative processes, but with inhibition of anabolic processes. Plasma adropin concentrations may thus reflect hepatic lipoprotein production and activation of metabolic stress responses across human tissues.
ISSN:2212-8778

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