Defective Olfactomedin-2 connects adipocyte dysfunction to obesity

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 and Francisco J. Ortega ()
Additional contact information
Aina Lluch: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Jèssica Latorre: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Isabel Espadas: University Pablo de Olavide
Núria Oliveras-Cañellas: Institut d’Investigació Biomèdica de Girona (IDIBGI)
José M. Moreno-Navarrete: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Estefanía Caballano-Infantes: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Gitalee Sarker: University of Oxford
Nicolás F. Malvido: University of Santiago de Compostela
Pablo Garrido-Gil: University of Santiago de Compostela
José L. Labandeira-García: University of Santiago de Compostela
Naoki Nakaya: National Institutes of Health
Silvia Mora: University of Barcelona
Eduardo Chicano: University of Cordoba, Reina Sofia University Hospital
Jaime López-Alcalá: University of Cordoba, Reina Sofia University Hospital
María M. Malagón: Instituto de Salud Carlos III (ISCIII)
Alejandro Martín-Montalvo: University Pablo de Olavide
Birong Zhang: Cardiff University
You Zhou: Cardiff University
Ana I. Domingos: University of Oxford
Miguel López: Instituto de Salud Carlos III (ISCIII)
Johanna Pörschke: Philipps University
María Gómez-Serrano: Philipps University
Witold Szymanski: Philipps University
Johannes Graumann: Philipps University
Stanislav I. Tomarev: National Institutes of Health
Ismael González-García: Instituto de Salud Carlos III (ISCIII)
José M. Fernández-Real: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Francisco J. Ortega: Institut d’Investigació Biomèdica de Girona (IDIBGI)

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62430-5

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