ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis
journal contributionposted on 2016-02-17, 00:00 authored by T. Izawa, N. Rohatgi, T. Fukunaga, QT Wang, MJ Silva, MJ Gardner, ML McDaniel, NA Abumrad, CF Semenkovich, SL Teitelbaum, W. Zou
ASXL2 is an ETP family protein that interacts with PPARγ. We find that ASXL2-/- mice are insulin resistant, lipodystrophic, and fail to respond to a high-fat diet. Consistent with genetic variation at the ASXL2 locus and human bone mineral density, ASXL2-/- mice are also severely osteopetrotic because of failed osteoclast differentiation attended by normal bone formation. ASXL2 regulates the osteoclast via two distinct signaling pathways. It induces osteoclast formation in a PPARγ/c-Fos-dependent manner and is required for RANK ligand- and thiazolidinedione-induced bone resorption independent of PGC-1β. ASXL2 also promotes osteoclast mitochondrial biogenesis in a process mediated by PGC-1β but independent of c-Fos. Thus, ASXL2 is a master regulator of skeletal, lipid, and glucose homeostasis.