Defective Olfactomedin-2 connects adipocyte dysfunction to obesity
Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity.
Authors
- You Zhou (ORCID: https://orcid.org/0000-0002-1743-1291)
- José L. Labandeira‐García (ORCID: https://orcid.org/0000-0002-8243-9791)
- Birong Zhang
- Gitalee Sarker (ORCID: https://orcid.org/0000-0002-2175-8705)
- Jaime López‐Alcalá (ORCID: https://orcid.org/0000-0001-5843-669X)
- Marı́a M. Malagón (ORCID: https://orcid.org/0000-0002-2419-2727)
- Estefanía Caballano‐Infantes (ORCID: https://orcid.org/0000-0001-8269-9158)
- Ismael González‐García (ORCID: https://orcid.org/0000-0002-5545-5841)
- Aina Lluch (ORCID: https://orcid.org/0000-0003-4216-4436)
- Jèssica Latorre (ORCID: https://orcid.org/0000-0002-7603-1458)
- Alejandro Martín‐Montalvo (ORCID: https://orcid.org/0000-0002-3886-5355)
- Núria Oliveras‐Cañellas (ORCID: https://orcid.org/0000-0002-7758-3326)
- Sílvia Mora (ORCID: https://orcid.org/0000-0002-8473-1497)
- Isabel Espadas (ORCID: https://orcid.org/0000-0002-9811-9717)
- Pablo Garrido‐Gil (ORCID: https://orcid.org/0000-0001-7734-8783)
- María Gómez‐Serrano (ORCID: https://orcid.org/0000-0002-9669-091X)
- Ana I. Domingos (ORCID: https://orcid.org/0000-0002-7938-4814)
- Eduardo Chicano‐Gálvez (ORCID: https://orcid.org/0000-0002-9481-9628)
- Johannes Graumann (ORCID: https://orcid.org/0000-0002-3015-5850)
- Francisco Ortega (ORCID: https://orcid.org/0000-0003-2111-769X)
- Stanislav I. Tomarev (ORCID: https://orcid.org/0000-0003-3042-8502)
- José María Moreno‐Navarrete (ORCID: https://orcid.org/0000-0002-2883-511X)
- Witold Szymański (ORCID: https://orcid.org/0000-0002-1202-3299)
- José Manuel Fernández‐Real (ORCID: https://orcid.org/0000-0002-7442-9323)
- Miguel López (ORCID: https://orcid.org/0000-0002-7823-1648)
- Naoki Nakaya
- Johanna Pörschke
- Nicolás F Malvido
Institutions
- National Institutes of Health (US)
- Consejo Superior de Investigaciones Científicas (ES)
- Universidade de Santiago de Compostela (ES)
- Universitat de Girona (ES)
- Instituto de Salud Carlos III (ES)
- University of Oxford (GB)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Institut d'Investigació Biomèdica de Girona (ES)
- National Eye Institute (US)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Universitat de Barcelona (ES)
- Cardiff University (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1038/s41467-025-62430-5
- Citations
- 1
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- Ministerio de Ciencia, Innovación y Universidades
- Centres de Recerca de Catalunya
- European Commission
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Xunta de Galicia
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición
- National Institutes of Health
- Instituto de Salud Carlos III
- European Regional Development Fund
- National Eye Institute