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

## TL;DR

This study shows how fat cells control blood cell production and bone growth through a key pathway, offering new treatment targets for diseases linked to fat cell dysfunction.

## Contribution

The study reveals a hypoxia-driven signaling network in adipocytes that regulates hematopoiesis and osteogenesis via SCF and chemerin.

## Key findings

- VHL deficiency in adipocytes causes systemic autoinflammation, disrupted hematopoiesis, and increased bone mass.
- SCF overexpression in VHL-deficient adipocytes disrupts hematopoietic stem cell quiescence.
- Chemerin production in adipocytes promotes osteogenesis via Wnt/β-catenin activation and is a key link to pathological bone growth.

## 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.

The VHL‐HIF2α (VHL is Von Hippel‐Lindau) axis in adipocytes differentially regulates hematopoiesis and bone formation through stem cell factor (SCF) and chemerin, respectively. This hypoxia‐responsive pathway in adipocytes establishes a systemic signaling network with HSCs and MSCs to maintain tissue homeostasis, revealing a targetable axis for treating disorders linked to adipocyte dysfunction.