Defective Olfactomedin-2 connects adipocyte dysfunction to obesity
Abstract 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. Funct...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62430-5 |
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| author | Aina Lluch Jèssica Latorre Isabel Espadas Núria Oliveras-Cañellas José M. Moreno-Navarrete Estefanía Caballano-Infantes Gitalee Sarker Nicolás F. Malvido Pablo Garrido-Gil José L. Labandeira-García Naoki Nakaya Silvia Mora Eduardo Chicano Jaime López-Alcalá María M. Malagón Alejandro Martín-Montalvo Birong Zhang You Zhou Ana I. Domingos Miguel López Johanna Pörschke María Gómez-Serrano Witold Szymanski Johannes Graumann Stanislav I. Tomarev Ismael González-García José M. Fernández-Real Francisco J. Ortega |
| author_facet | Aina Lluch Jèssica Latorre Isabel Espadas Núria Oliveras-Cañellas José M. Moreno-Navarrete Estefanía Caballano-Infantes Gitalee Sarker Nicolás F. Malvido Pablo Garrido-Gil José L. Labandeira-García Naoki Nakaya Silvia Mora Eduardo Chicano Jaime López-Alcalá María M. Malagón Alejandro Martín-Montalvo Birong Zhang You Zhou Ana I. Domingos Miguel López Johanna Pörschke María Gómez-Serrano Witold Szymanski Johannes Graumann Stanislav I. Tomarev Ismael González-García José M. Fernández-Real Francisco J. Ortega |
| author_sort | Aina Lluch |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-21cfff4c7e724f14b3cf01d2d21b1069 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-21cfff4c7e724f14b3cf01d2d21b10692025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-08-0116112510.1038/s41467-025-62430-5Defective Olfactomedin-2 connects adipocyte dysfunction to obesityAina Lluch0Jèssica Latorre1Isabel Espadas2Núria Oliveras-Cañellas3José M. Moreno-Navarrete4Estefanía Caballano-Infantes5Gitalee Sarker6Nicolás F. Malvido7Pablo Garrido-Gil8José L. Labandeira-García9Naoki Nakaya10Silvia Mora11Eduardo Chicano12Jaime López-Alcalá13María M. Malagón14Alejandro Martín-Montalvo15Birong Zhang16You Zhou17Ana I. Domingos18Miguel López19Johanna Pörschke20María Gómez-Serrano21Witold Szymanski22Johannes Graumann23Stanislav I. Tomarev24Ismael González-García25José M. Fernández-Real26Francisco J. Ortega27Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), University Pablo de OlavideService of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Department of Physiology, Anatomy and Genetics, University of OxfordDepartment of Physiology, CiMUS, University of Santiago de CompostelaInstituto de Investigación Sanitaria de Santiago de Compostela (IDIS), CiMUS, University of Santiago de CompostelaInstituto de Investigación Sanitaria de Santiago de Compostela (IDIS), CiMUS, University of Santiago de CompostelaSection on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of HealthDepartment of Biochemistry and Molecular Biomedicine, University of BarcelonaDepartment of Cell Biology, Physiology and Immunology, Instituto Maimonides de Investigación Biomedica de Córdoba (IMIBIC), University of Cordoba, Reina Sofia University HospitalDepartment of Cell Biology, Physiology and Immunology, Instituto Maimonides de Investigación Biomedica de Córdoba (IMIBIC), University of Cordoba, Reina Sofia University HospitalCIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII)Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), University Pablo de OlavideSystems Immunity Research Institute, Cardiff UniversitySystems Immunity Research Institute, Cardiff UniversityDepartment of Physiology, Anatomy and Genetics, University of OxfordCIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII)Institute for Tumor Immunology, Center for Tumor Biology and Immunology, Philipps UniversityInstitute for Tumor Immunology, Center for Tumor Biology and Immunology, Philipps UniversityInstitute of Translational Proteomics & Core Facility Translational Proteomics, Biochemical/Pharmacological Centre, Philipps UniversityInstitute of Translational Proteomics & Core Facility Translational Proteomics, Biochemical/Pharmacological Centre, Philipps UniversitySection on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of HealthCIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII)Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IDIBGI)Abstract 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.https://doi.org/10.1038/s41467-025-62430-5 |
| spellingShingle | Aina Lluch Jèssica Latorre Isabel Espadas Núria Oliveras-Cañellas José M. Moreno-Navarrete Estefanía Caballano-Infantes Gitalee Sarker Nicolás F. Malvido Pablo Garrido-Gil José L. Labandeira-García Naoki Nakaya Silvia Mora Eduardo Chicano Jaime López-Alcalá María M. Malagón Alejandro Martín-Montalvo Birong Zhang You Zhou Ana I. Domingos Miguel López Johanna Pörschke María Gómez-Serrano Witold Szymanski Johannes Graumann Stanislav I. Tomarev Ismael González-García José M. Fernández-Real Francisco J. Ortega Defective Olfactomedin-2 connects adipocyte dysfunction to obesity Nature Communications |
| title | Defective Olfactomedin-2 connects adipocyte dysfunction to obesity |
| title_full | Defective Olfactomedin-2 connects adipocyte dysfunction to obesity |
| title_fullStr | Defective Olfactomedin-2 connects adipocyte dysfunction to obesity |
| title_full_unstemmed | Defective Olfactomedin-2 connects adipocyte dysfunction to obesity |
| title_short | Defective Olfactomedin-2 connects adipocyte dysfunction to obesity |
| title_sort | defective olfactomedin 2 connects adipocyte dysfunction to obesity |
| url | https://doi.org/10.1038/s41467-025-62430-5 |
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