Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33800-0
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Funding
- National Key R&D Program of Ministry of Science and Technology of the People's Republic of China [2021YFA0804801, 2018YFA0800702]
- National Natural Science Foundation of China [91642113, 31671227]
- Thousand Young Talents Program of the Chinese government
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This study reveals that adipose tissue fibrosis is associated with metabolic dysfunction in obesity. The Hippo pathway interacts with TGF-beta signaling to regulate the cellular and functional shift of adipocytes, promoting extracellular matrix remodeling and the development of adipose tissue fibrosis. Macrophages produce TGF-beta and YAP/TAZ enhance SMAD2 stability, thereby contributing to fibrotic responses. Inhibition of YAP/TAZ activity can relieve adipose tissue fibrosis and improve metabolic homeostasis in obese mice.
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGF beta stimulation. Fibrosis disrupts adipose tissue (AT) homeostasis and exacerbates metabolic dysfunction upon chronic caloric excess. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGF beta signaling to orchestrate a cellular and/or functional shift of adipocytes from energy storage to extracellular matrix (ECM) remodeling in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4(+) progenitor cells and convert to DPP4(-) myofibroblasts upon TGF beta stimulation. On the other hand, Hippo pathway inhibition during obesity impaired adipocyte identity while promoted ECM remodeling activity of adipocytes. Macrophages recruited by CCL2 produced TGF beta to accelerate AT fibrosis. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target.
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