Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue
Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
Authors
- José J.G. Marı́n (ORCID: https://orcid.org/0000-0003-1186-6849)
- Nicholas S. Berrow (ORCID: https://orcid.org/0000-0002-6104-4117)
- Arkaitz Carracedo Pérez (ORCID: https://orcid.org/0009-0006-2939-1377)
- David Sebastián (ORCID: https://orcid.org/0000-0002-7260-3869)
- Óscar Reina (ORCID: https://orcid.org/0000-0002-1031-2732)
- Montserrat Romero (ORCID: https://orcid.org/0000-0002-2801-6376)
- Manuel Palacı́n (ORCID: https://orcid.org/0000-0002-8670-293X)
- Per Antonson (ORCID: https://orcid.org/0000-0001-9335-9941)
- Luis Rodrigo Cataldo (ORCID: https://orcid.org/0000-0003-1225-414X)
- Alba Sabaté-Pérez (ORCID: https://orcid.org/0000-0001-8257-6406)
- Rémy Burcelin (ORCID: https://orcid.org/0000-0002-7942-8346)
- Hans Burghardt
- María J. Monte (ORCID: https://orcid.org/0000-0003-1844-7428)
- António Zorzano (ORCID: https://orcid.org/0000-0002-1638-0306)
- Sónia R. Veiga (ORCID: https://orcid.org/0000-0003-0115-7651)
- Manuela Sánchez‐Feutrie
- Jan-Ακε Gustafsson (ORCID: https://orcid.org/0000-0002-1472-1373)
- Vanessa Hernández (ORCID: https://orcid.org/0009-0008-0824-0814)
- Natàlia Plana
- Núria Borràs-Ferré
- Laura Isabel Alcaide
- Martina Ràfols
- Noemí Giménez
- Andrea Rodgers-Furones
Institutions
- University of Copenhagen (DK)
- Radboud University Nijmegen (NL)
- Inserm (FR)
- Universidad de Salamanca (ES)
- Lund University (SE)
- Novo Nordisk Foundation (DK)
- Instituto de Salud Carlos III (ES)
- Erasmus MC (NL)
- Radboud University Medical Center (NL)
- Karolinska Institutet (SE)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Integrated Cardio Metabolic Centre (SE)
- Radboud Institute for Molecular Life Sciences (NL)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Institute for Research in Biomedicine (ES)
- Hôpital Rangueil (FR)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- University of Houston (US)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-04
- DOI
- https://doi.org/10.1038/s41467-025-62255-2
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundación BBVA
- Institute for Research in Biomedicine
- “la Caixa” Foundation
- French Muscular Dystrophy Association
- Centres de Recerca de Catalunya
- European Foundation for the Study of Diabetes
- Generalitat de Catalunya
- Institució Catalana de Recerca i Estudis Avançats
- Ministerio de Ciencia e Innovación
- Banco Bilbao Vizcaya Argentaria
- Ministério da Ciência, Tecnologia e Ensino Superior
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- Instituto de Salud Carlos III