Bifurcate Regulation of Hematopoietic Homeostasis and Bone Osteogenesis by VHL‐HIF2α‐Controlled Adipocyte Function

Abstract Adipocytes play a pivotal role in maintaining metabolic and immunological homeostasis. Here, this work shows that VHL‐HIF2α (VHL is Von Hippel‐Lindau) axis in mature adipocytes regulates hematopoiesis and osteogenesis. Genetic ablation of VHL in adipocytes triggers profound systemic autoinflammation and abnormal hematopoiesis, concomitant with fat mass decrease and pathological elevation of bone mass. On one hand, VHL deficiency results in aberrantly high stem cell factor (SCF) expression in adipocytes, which exerts a negative role for hematopoietic homeostasis through disrupting hematopoietic stem cell (HSC) quiescence. In vivo anti‐CD117 monoclonal antibody treatment ameliorates the hematopoietic defects in VHL‐deficient mice. On the other hand, direct HIF2α binding to hypoxia‐response elements in the Rarres2 locus enhances chemerin production in adipocytes, which facilitates mesenchymal stem cell (MSC) osteogenesis via Wnt/β‐catenin activation. Pharmacological chemerin neutralization through CMKLR1 inhibition using α‐NETA mitigates osteogenic activity both in vitro and in vivo. This work thus identifies chemerin as the pivotal molecular nexus connecting hypoxic adipocyte dysfunction to pathological osteosclerosis. The findings uncover a hypoxia‐driven signaling network in adipocytes that orchestrates cross‐talk with both HSCs and MSCs to regulate systemic homeostasis, thereby revealing therapeutic targets for disorders associated with adipocyte dysfunction.