Knockdown of a disintegrin A metalloprotease 12 (ADAM12) during adipogenesis reduces cell numbers, delays differentiation, and increases lipid accumulation in 3T3-L1 cells

Chantal A. Coles, Jovana Maksimovic, Jenny Wadeson, Fahri T. Fahri, Tracie Webster, Carolina Leyton, Matthew B. McDonagh, Jason D. White

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    Abstract

    Mouse models have shown that a disintegrin A metalloprotease 12 (ADAM12) is implicated during adipogenesis; the molecular pathways are not well understood. Stealth RNA interference was used to knock down ADAM12 in 3T3-L1 cells. Using gene profiling and metabolic enzymatic markers, we have identified signaling pathways ADAM12 impacts upon during proliferation, differentiation, and maturation of adipocytes. ADAM12 reduced cell numbers in proliferating preadipocytes, delayed differentiation of preadipocytes to adipocytes, and increased lipid accumulation in mature adipocytes. The pathway most affected by ADAM12 knockdown was regulation of insulin-like growth factor (IGF) activity by insulin-like growth factor binding proteins (IGFBPs); ADAM12 is known to cleave IGFBP3 and IGFBP5. The IGF/mTOR signaling pathway was down-regulated, supporting a role for ADAM12 in the IGFBP/IGF/mTOR-growth pathway. PPARγ signaling was also down-regulated by ADAM12 knockdown. Gene ontology (GO) analysis revealed that the extracellular matrix was the cellular compartment most impacted. Filtering for matrisome genes, connective tissue growth factor (Ctgf) was up-regulated. CTGF and IGBP3 can interact with PPARγ to hinder its regulation. Increased expression of these molecules could have influenced PPARγ signaling reducing differentiation and an imbalance of lipids. We believe ADAM12 regulates cell proliferation of preadipocytes through IGFBP/IGF/mTOR signaling and delays differentiation through altered PPAR signaling to cause an imbalance of lipids within mature adipocytes.
    Original languageEnglish
    Pages (from-to)1839-1855
    Number of pages17
    JournalMolecular Biology of the Cell
    Volume29
    Issue number15
    Early online date30 Jul 2018
    DOIs
    Publication statusPublished - 01 Aug 2018

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