ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis
2015
Takashi Izawa | Nidhi Rohatgi | Tomohiro Fukunaga | Qun-Tian Wang | Matthew J. Silva | Michael J. Gardner | Michael L. McDaniel | Nada A. Abumrad | Clay F. Semenkovich | Steven L. Teitelbaum | Wei 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.
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