Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating

Yan Tao1, Jinhao Zang1, Tianci Wang1

  • 1Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

Nature Communications
|August 14, 2025
PubMed

Insights

Loss of TIPE2 in macrophages worsens obesity by promoting adipose stem cell ferroptosis. Restoring TIPE2 in macrophages protects against metabolic disorders by preventing cell death.

Area of Science:

  • Immunology
  • Metabolic Diseases
  • Cell Biology

Background:

  • Morbid obesity leads to adipose stem cell (ASC) shortage, disrupting visceral adipose tissue (VAT) homeostasis.
  • The role of macrophages and TNF-α-induced protein 8-like 2 (TIPE2) in VAT macrophage-ASC crosstalk and ASC shortage is unclear.

Purpose of the Study:

  • To investigate the function of TIPE2 in VAT macrophages and its role in macrophage-ASC crosstalk.
  • To explore the potential of targeting macrophage TIPE2 as a therapeutic strategy for obesity-related diseases.

Main Methods:

  • Utilized male mice models with diet-induced obesity.
  • Manipulated TIPE2 expression in VAT macrophages.
  • Analyzed ASC ferroptosis, mitochondrial function, and intercellular communication via exosomes.

Main Results:

  • TIPE2 deficiency in VAT macrophages promoted ASC ferroptosis, exacerbating obesity and metabolic disorders.
  • Macrophage-specific TIPE2 restoration corrected these metabolic impairments.
  • TIPE2-deficient macrophages induced mitochondrial fragmentation and reduced exosomal ferritin, leading to ROS and Fe2+ overload in ASCs, causing ferroptosis.

Conclusions:

  • Macrophage TIPE2 restrains the IP3R-Ca2+-Drp1 axis, preventing excessive mitochondrial fission and protecting ASCs from ferroptosis.
  • Distinct obesity-associated macrophages dictate ASC ferroptosis.
  • Macrophage TIPE2 represents a potential therapeutic target for obesity and associated metabolic diseases.