GREM2 is associated with human central obesity and inhibits visceral preadipocyte browning

Background Some circulating proteins are linked to central adiposity. Gremlin 2 (GREM2) functions as a secreted factor involved in osteogenesis and adipogenesis. Here, we investigated the association of blood GREM2 levels and central adiposity, and the biological roles of GREM2 in the browning program of visceral preadipocytes. Methods Three independent cohorts were applied to detect circulating GREM2 levels. Recombinant Grem2 protein, Grem2 overexpression and knockout mouse models, and preadipocyte-specific Bmpr2 knockout mice were used to assess the roles of Grem2 in the browning program. Findings We detected the presence of GREM2 protein in human serum using an ELISA approach. We revealed ele-vated GREM2 levels in severely obese subjects and validated this finding in a large-scale community population involving 10,327 subjects. Notably, serum GREM2 was positively associated with visceral fat volume, as quantified by 3D reconstruction methods. In mice, Grem2 was highly expressed in visceral fat and liver tissues, while surgical removal of visceral fat lowered circulating Grem2 levels. Visceral fat secreted more Grem2 in obese mice. Grem2- overexpressed mice exhibited a reduced browning ability of visceral fat, whereas Grem2 ablation enhanced the browning capacity and reduced visceral fat content. Mechanistically, Grem2 attenuated the browning program of vis-ceral preadipocytes partially by antagonizing BMP4/7-SMAD1/5/8 signaling pathway. Further, genetic deletion of Bmpr2 in Pdgfra+ preadipocytes abolished the antagonistic effect of Grem2. Interpretation These findings indicate that GREM2 might function as a circulating protein factor associated with human visceral adiposity, and Grem2 inhibits the browning capacity of visceral preadipocytes partially by BMP4/7-BMPR2 signaling pathway. Copyright (c) 2022 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/) eBioMedicine 103969 Published https://doi.org/10.1016/j. ebiom.2022.103969