ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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. ASXL2 regulates glucose homeostasis, adipogenesis, and osteoclast differentiation by activating PPARγ. Izawa et al. find that ASXL2-deficient mice are insulin resistant, lipodystrophic, and osteopetrotic. ASXL2 promotes osteoclast formation in a Fos-dependent manner independent of PGC-1β. ASXL2 enhances osteoclast mitochondrial biogenesis in a process mediated by PGC-1β but independent of c-Fos.

Original languageEnglish
Pages (from-to)1625-1637
Number of pages13
JournalCell Reports
Volume11
Issue number10
DOIs
Publication statusPublished - Jun 16 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Izawa, T., Rohatgi, N., Fukunaga, T., Wang, Q. T., Silva, M. J., Gardner, M. J., McDaniel, M. L., Abumrad, N. A., Semenkovich, C. F., Teitelbaum, S. L., & Zou, W. (2015). ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. Cell Reports, 11(10), 1625-1637. https://doi.org/10.1016/j.celrep.2015.05.019