Abstract
The extracellular matrix (ECM) maintenance is crucial to the structural integrity of adipocytes and whole adipose tissue formation. However, the potential impact of the ECM on adipocyte lineage commitment is unclear. Herein, we demonstrate that forced expression of matrix-associated metalloproteinase Adamts1 (a disintegrin and metalloproteinase with thrombospondin motifs 1), which we show is targeted by microRNA-181d (miR-181d) during BMP4-induced adipocytic lineage commitment, markedly impairs adipocyte commitment. Conversely, siRNA-induced inhibition of Adamts1 promotes adipocyte commitment. Adamst1 metalloprotease activity is required for this inhibition and is determined to function via remodeling ECM components followed by activating FAK–ERK signaling pathway during the commitment process. Furthermore, ablation of Adamts1 in adipose tissue increases adipose tissue mass, reduces insulin sensitivity, and disrupts lipid homeostasis. This finding is consistent with Adamts1 decreased expression in the adipose tissue of obese mice and an inverse correlation of Adamts1 expression with body mass index in humans. Collectively, our results indicate that Adamts1 acts as an ECM ‘modifier’, with miR-181d-induced downregulation, that regulates adipocyte lineage commitment and obesity.
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Abbreviations
- Adamts1:
-
a disintegrin and metalloproteinase with thrombospondin motifs 1
- ECM:
-
extracellular matrix
- BMI:
-
body mass index
- HFD:
-
high-fat-diet
- iWAT:
-
inguinal white adipoge tissue
- eWAT:
-
epididymal white adipoge tissue
- BAT:
-
brown adipose tissue
- SVF:
-
stromal vascular fraction
- MMPs:
-
matrix metalloproteases
- MSCs:
-
mesenchymal stem cells
- ERK1/2:
-
extracellular signal-regulated kinases 1 and 2
- FAK:
-
focal adhesion kinase
- BMP4:
-
bone morphogenetic protein 4
- Pref1:
-
preadipocyte factor 1
- PPARγ:
-
peroxisome proliferator-activated receptor γ
- C/EBPα:
-
CCAAT enhancer-binding protein α
- 422/aP2:
-
fatty acid-binding protein
- GTT:
-
glucose tolerance tests
- ITT:
-
insulin tolerance tests
- LDL-C:
-
low-density lipoprotein-cholesterol
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Acknowledgements
The patients’ samples of adipose tissue were kindly provided by Weiping Jia and Cheng Hu from Shanghai Jiaotong University Affiliated Sixth People’s Hospital. This research was partially supported by National Key Basic Research Project Grant 2011CB910201, the State Key Program of National Natural Science Foundation 3100048C120114, and National Natural Science Foundation 81390350 (to QQ Tang.); by National Natural Science Foundation Grant 31271489 and 81170781 (to HY Huang.); by the Joint Research Fund for Overseas, Hong Kong and Macao Young Scholars (3132801) and the NIDDK-funded Minnesota Obesity Center (P30DK050456); by National Natural Science Foundation of China Grant J1210041(to RZ Qian.). The department of biochemistry is supported by Shanghai Leading Academic Discipline Project, Project Number: B110 and by 985 Project 985III-YFX0302.
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Chen, SZ., Ning, LF., Xu, X. et al. The miR-181d-regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling. Cell Death Differ 23, 1778–1791 (2016). https://doi.org/10.1038/cdd.2016.66
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DOI: https://doi.org/10.1038/cdd.2016.66
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