TY - JOUR
T1 - ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis
AU - Izawa, Takashi
AU - Rohatgi, Nidhi
AU - Fukunaga, Tomohiro
AU - Wang, Qun Tian
AU - Silva, Matthew J.
AU - Gardner, Michael J.
AU - McDaniel, Michael L.
AU - Abumrad, Nada A.
AU - Semenkovich, Clay F.
AU - Teitelbaum, Steven L.
AU - Zou, Wei
N1 - Funding Information:
This work was supported by NIH grants DK076729, DK56341, and DK20579 (to C.F.S.); 5R01AR050211 (to M.J.S.); 5R01AR03278828, 5R01AR05703705, and 5R37AR04652315 (to S.L.T.); P30AR057235 and P30DK056341 and Shriners Hospitals for Children grant 85400-STL (to S.L.T.). The authors wish to thank Evan Buettmann, Tarpit Patel, Soumya Ravindran, and Jean Chappel. We thank Thomas L. Clemens for providing InR flox/flox bones and Gerard Karsenty for reviewing the manuscript.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/6/16
Y1 - 2015/6/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.05.019
DO - 10.1016/j.celrep.2015.05.019
M3 - Article
C2 - 26051940
AN - SCOPUS:84937632908
SN - 2211-1247
VL - 11
SP - 1625
EP - 1637
JO - Cell Reports
JF - Cell Reports
IS - 10
ER -