The Histone Demethylase KDM6B Governs the LYVE1+ Perivascular Macrophage Phenotype to Control Adipose Tissue Expandability through BMP2 signaling

The capacity of white adipose tissue (WAT) to expand in response to energy surplus is a key factor in determining metabolic health. In obesity, this expansion becomes dysregulated and contributes to metabolic dysfunction, insulin resistance and type 2 diabetes. Phenotypically diverse subtypes of adipose tissue macrophages (ATMs) control WAT plasticity, yet the underlying regulatory mechanisms and factors have remained enigmatic. Here, we identify the lysine demethylase KDM6B (aka JMJD3) as an essential epigenetic and transcriptional regulator that specifies ATM phenotypes during WAT expansion. We first show that KDM6B expression in human ATMs correlates with insulin sensitivity, glycemic control and levels of WAT inflammation. Single-cell RNA sequencing of both human and mouse ATMs revealed that KDM6B is predominantly expressed in LYVE1⁺CD206⁺ perivascular macrophages (PVMs), where it is essential for their maintenance and endocytic function. Myeloid-specific depletion of Kdm6b in mice triggers a phenotypic shift of PVMs, resulting in accumulation of CD9⁺CD63⁺ lipid-associated macrophages (LAMs) and impaired WAT expansion marked by adipocyte hypertrophy, vascular rarefaction and increased inflammation. Consequently, Kdm6b-deficient mice develop pronounced insulin resistance and a pro-diabetic state when exposed to a high-fat diet. We uncover that KDM6B governs the transcriptional program of PVMs, including the regulation of adipogenesis, through BMP2 signaling. Mechanistically, KDM6B directly regulates Bmp2 expression in PVMs through demethylation of H3K27me3 at the Bmp2 promoter. Myeloid-specific depletion of Bmp2 partially mimics the WAT phenotype seen in Kdm6b-deficient mice, characterized by adipocyte hypertrophy. Overall, our study identifies the KDM6B–BMP2 axis as an ATM-intrinsic epigenetic and transcriptional regulator that couples immune cell phenotypes to WAT expandability and metabolic health.