What question did this study set out to answer?

This research aims to explore how the lipokine 12,13-diHOME from brown adipose tissue regulates macrophage recruitment during cold exposure.

June 7, 2026

2529-P: A Brown Adipose Tissue–Derived Lipokine Signals through a Novel GPCR to Regulate Macrophage Recruitment during Cold Exposure

Key Points

This research aims to explore how the lipokine 12,13-diHOME from brown adipose tissue regulates macrophage recruitment during cold exposure.
Conducted a GPCR screen to identify candidate receptors for 12,13-diHOME.
Analyzed single-cell RNA sequencing data from mice under different temperature conditions.
Performed in vivo and ex vivo experiments using bone marrow chimeric mice and migration assays with BM-derived macrophages.
Identified a specific GPCR highly responsive to 12,13-diHOME.
Cold exposure increased macrophage populations in BAT, specifically expressing the identified receptor.
Macrophage accumulation in BAT after cold exposure was significantly reduced in BM lacking the GPCR.

Abstract

Introduction and Objective: Brown adipose tissue (BAT) is a promising target for metabolic diseases due to its thermogenic and endocrine functions. Beyond heat production, BAT secretes signaling molecules such as the lipokine, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which is induced by cold and exercise. 12,13-diHOME exerts metabolic benefits, yet the molecular signaling mechanisms mediating these effects remain elusive. Methods: To identify signaling pathways for 12,13-diHOME, we performed a G protein-coupled receptor (GPCR) screen to identify candidate receptors. We then analyzed single-cell RNA sequencing (scRNA-seq) data from BAT of mice housed at thermoneutrality or cold environment to determine cell-type-specific receptor expression. Guided by these findings, we conducted complementary in vivo and ex vivo experiments using bone marrow (BM) chimeric mice, flow cytometric profiling, and migration assays with BM-derived macrophages (BMDM) to investigate the functional role of this signaling axis. Results: We identified a previously uncharacterized GPCR with high specificity for 12,13-diHOME. scRNA-seq analysis revealed that cold exposure increased BAT macrophages enriched for this receptor. Using BM transplantation, we demonstrated that cold-induced macrophage accumulation in BAT originated from circulating BM-derived cells. Importantly, mice receiving BM lacking the GPCR failed to exhibit enhanced macrophage recruitment to BAT after cold exposure. Additionally, 12,13-diHOME and co-culture with brown adipocytes promoted BMDM migration, an effect that was absent in the receptor-deficient cells. Conclusion: These findings uncover a novel ligand-receptor signaling pathway through which the BAT-derived lipokine 12,13-diHOME drives macrophage recruitment during cold exposure, providing new insight into metabolite-mediated cell-cell communication that shapes BAT function and its metabolic impact. Disclosure B.I. Park: None. S. Chen: None. Y. Tseng: Consultant; Ended; Paratus Sciences. Consultant; Current; Sofinova Partners. F. Alvarez-Gallego: None. J.I. Senfeld: Employee; Current; Eli Lilly and Company. Funding NIH Training Grant (T32 DK007260), Joslin Diabetes Center DRC (NIDDK P30 DK036836)

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