title: The miR-181d-regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.
authors.forename: L-F
authors.initials: LF
authors.lastname: Ning
authors.affiliation: Institute of Stem Cell Research and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.
authors.forename: C
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China.
authors.forename: W-P
authors.initials: WP
authors.lastname: Jia
authors.affiliation: Department of Food Science and Nutrition, University of Minnesota-Twin Cities, Saint Paul, MN 55108, USA.
authors.forename: X-L
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.|Institute of Stem Cell Research and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, China.|Institute of Stem Cell Research and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Huang
mesh_terms: D000071097:ADAMTS1 Protein / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D019070:Cell Lineage / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D055815:Young Adult
chemical_list: D055415:Bone Morphogenetic Protein 4; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D000071097:ADAMTS1 Protein