The Hippo pathway controls adipose tissue fibrosis

Adipose tissue fibrosis is an important feature of severe obesity and a key obstacle to reverse obesity; However, the core cellular molecular mechanism of its development is not clear
.
Adipose tissue fibrosis manifests as excessive accumulation of diseased extracellular matrix (ECM), which limits the physical space for adipocyte growth, disrupts cell-to-cell communication, and exerts shear forces
on adipocyte membranes 。 As a result, the plasticity of fat cells is impaired, and the characteristics of fat are gradually lost, which is not conducive to their storage and mobilization of excess energy; The secretion of inflammatory factors increases correspondingly, further worsening the microenvironment of adipose tissue, disrupting tissue homeostasis, accelerating the progression of fibrosis, and forming a vicious circle
.
A large number of studies have shown that the Hippo pathway is the core pathway
for regulating organ size and tissue homeostasis.
Activating the upstream kinase LATS1/2 of the Hippo pathway promotes phosphorylation of the transcriptional co-activating protein YAP/TAC, which in turn leads to YAP/TAZ being detained in the cytoplasm and degraded
。 The non-phosphorylated form of YAP/TAZ binds to transcription factors such as TEAD after transport into the nucleus to promote downstream gene expression
.
But whether and how the Hippo pathway regulates adipose tissue fibrosis remains to be elucidated
.

On October 13, 2022, the team of Qiu Yifu from the School of Future Technology/Life Science Joint Center of Peking University was there Nature Communications published a research paper entitled The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis [1
。 The paper reports that the Hippo signaling pathway plays a key role in maintaining the properties of adipocytes, and when they are inactivated, the energy-storing adipocytes will be remodeled into myofibroblasts that produce the extracellular matrix, thereby synergizing with TGFβ signaling to promote adipose tissue fibrosis
.

The authors first found that in ob/ob hereditary obese mice and high-fat diet-induced obese mice, the LATS kinase of fat was partially inactivated, and YAP/TAZ increased significantly.
It is positively correlated with
the expression of fibrosis genes.
To fully activate YAP/AZ, the authors specifically knocked out Lats1/2 (L1L2-KO) in mouse adipocytes and found that the mice experienced massive loss of adipocytes, fibrosis of adipose tissue, and a significant increase
in inflammation levels at an early age.
By further knocking out Yap/Taz on top of knocking out Lats1/2, the mice completely returned to normal
.
Transcriptome sequencing analysis found that fibrosis-related gene expression in subcutaneous adipocytes lacking Lats1/2 was significantly upregulated
.
Unexpectedly, knocking out Lats1/2 in tamoxifen-driven induced adult mouse models (L1L2-iAKO) also caused fat loss without fibrotic lesions
.
So, how does this phenotypic difference develop? The authors found that TGFβ signaling was significantly activated
in the adipose tissue of L1L2-AKO mice compared to L1L2-iAKO mice.
The authors specifically overexpressed the activated form of TGFβ receptor in adipocytes of L1L2-iAKO mice, which successfully induced lipofibrotic lesions
in adult mice.

    Cytomechanistic studies have found that macrophages are the main cellular source of TGFβ in adipose tissue; TGFβ secreted by macrophages activates SMAD2 protein
in adipocytes.
Cell tracing analysis showed that adipocytes lacking Lats1/2 were dedifferentiated into DPP4⁺ adipose precursor cells
.
Both in vitro culture and in vivo transplantation experiments showed that DPP4+ precursor cells differentiated into ^DPP-αSMA+ myofibroblasts under TGFβ stimulation.
The latter secretes a large amount of extracellular matrix, which promotes adipose tissue fibrosis
.
Molecular mechanism elucidation showed that when the Lats1/2 of fat cells were specifically knocked out, the phosphorylation inhibition of YAP/TAZ by LATS1/2 could be lifted, YAP/TAC By inhibiting the ubiquitination of SMAD2, the protein is stabilized, and complexes are formed with it and transported to the nucleus, which promotes the expression
of downstream fibrosis genes.
In addition, YAP/TAZ promotes the expression and secretion of chemokines such as CCL2/7, thereby recruiting macrophages to secrete more TGFβ, enhance fibrosis response, and form a macrophage-mediated positive feedback loop
.
These results show that the inactivation of the Hippo pathway and the activation of TGFβ signaling synergistically promote adipose tissue fibrosis, both of which are indispensable, and the inactivation of the Hippo pathway plays the role of the first signal (Fig.
1).

。

Fig.
1: Mechanism pattern of
Hippo pathway regulating adipose tissue fibrosis.

Finally, the authors found that knocking out Yap/Taz in adult mouse adipocytes significantly reduced adipose tissue fibrosis induced by a high-fat diet, and improved insulin sensitivity and glucose tolerance in mice
.
Injection of veteporfen, an inhibitor of YAP, in ob/ob hereditary obese mice and high-fat diet-induced obese mice, can also reduce the degree of fibrosis of adipose tissue and improve metabolic disorders
in mice.

In conclusion, the study found that the Hippo pathway controls adipose tissue fibrosis by influencing the plasticity of adipocytes, and TGFβ signaling derived from macrophages plays a synergistic role
in this process.
In addition, targeting the Hippo pathway can reduce adipose tissue fibrosis, improve insulin sensitivity and glucose tolerance, and provide a new strategy
for the prevention and treatment of obesity.

Shen Hongyu, PhD graduate of Peking University Institute of Advanced Interdisciplinary Disciplines, PhD student Huang Xun and PhD graduate Zhao Yiheng are the co-first authors of the paper, and Qiu Yifu, a researcher from the School of Future Technology/Peking University-Tsinghua Joint Center for Life Sciences, Peking University, is the corresponding author
.
Thanks to researcher Nan Tang of the Beijing Institute of Biological Sciences for generously donating Taz^flox mice
.

Qiu Yifu Laboratory of Peking University School of Future Technology/Peking University-Tsinghua Joint Center for Life Sciences has long been engaged in metabolic stress biology research, focusing on obesity and related metabolic diseases, from three aspects: immune regulation of energy metabolism, development and function of brown/beige fat, Dynamic remodeling
of adipose tissue.
In addition to the elucidating of the mechanism by which the hippo pathway regulates adipose tissue fibrosis, we have recently discovered the BioArt: Cell Metab | Qiu Yifu's team discovered a new mechanism of brown fat thermogenesis mediated by "thermogenesis channels") and revealed a new pathway for macrophages to regulate obesity and metabolic inflammation (BioArt: Nat Immunol | Qiu Yifu's team discovered a new mechanism by which IRX3 protein regulates obesity).

Now due to development needs, we are looking for postdoctoral fellows to engage in metabolic stress biology research
.
Prof.
Qiu Yifu is enrolled through the School of Future Technology of Peking University and the Peking University-Tsinghua Life Science Center, and welcomes graduate students to apply
.
If you are interested, please send your resume and other materials to: yifu.
qiu@pku.
edu.
cn
.