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The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis

Author

Listed:
  • Hongyu Shen

    (Peking University
    Peking University
    Peking University)

  • Xun Huang

    (Peking University
    Peking University
    Peking University)

  • Yiheng Zhao

    (Peking University
    Peking University
    Peking University)

  • Dongmei Wu

    (Peking University
    Peking University)

  • Kaili Xue

    (Peking University)

  • Jingfei Yao

    (Peking University)

  • Yushuang Wang

    (Peking University)

  • Nan Tang

    (National Institute of Biological Sciences
    Tsinghua University)

  • Yifu Qiu

    (Peking University
    Peking University)

Abstract

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 TGFβ 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 TGFβ 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 TGFβ 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.

Suggested Citation

  • Hongyu Shen & Xun Huang & Yiheng Zhao & Dongmei Wu & Kaili Xue & Jingfei Yao & Yushuang Wang & Nan Tang & Yifu Qiu, 2022. "The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33800-0
    DOI: 10.1038/s41467-022-33800-0
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    Cited by:

    1. Xun Huang & Xinmeng Li & Hongyu Shen & Yiheng Zhao & Zhao Zhou & Yushuang Wang & Jingfei Yao & Kaili Xue & Dongmei Wu & Yifu Qiu, 2023. "Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yaechan Song & Heeju Na & Seung Eon Lee & You Min Kim & Jihyun Moon & Tae Wook Nam & Yul Ji & Young Jin & Jae Hyung Park & Seok Chan Cho & Jaehoon Lee & Daehee Hwang & Sang-Jun Ha & Hyun Woo Park & Ja, 2024. "Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.

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