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Defective Olfactomedin-2 connects adipocyte dysfunction to obesity

Lluch, Aina, Latorre, Jèssica, Espadas, Isabel, Oliveras-Cañellas, Núria, Moreno-Navarrete, José M., Caballano-Infantes, Estefanía, Sarker, Gitalee, Malvido, Nicolás F., Garrido-Gil, Pablo, Labandeira-García, José L., Nakaya, Naoki, Mora, Silvia, Chicano, Eduardo, López-Alcalá, Jaime, Malagón, María M., Martín-Montalvo, Alejandro, Zhang, Birong, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Domingos, Ana I., López, Miguel, Pörschke, Johanna, Gómez-Serrano, María, Szymanski, Witold, Graumann, Johannes, Tomarev, Stanislav I., González-García, Ismael, Fernández-Real, José M. and Ortega, Francisco J. 2025. Defective Olfactomedin-2 connects adipocyte dysfunction to obesity. Nature Communications 16 (1) , 7154. 10.1038/s41467-025-62430-5

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Schools > Medicine
Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 12 August 2025
Date of Acceptance: 17 July 2025
Last Modified: 12 Aug 2025 10:47
URI: https://orca.cardiff.ac.uk/id/eprint/180373

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