Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bonederived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.
Bibliographical noteFunding Information:
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Grant numbers: AR056950, AR60140; National Institute of Diabetes and Digestive and Kidney Diseases, Grant numbers: Subaward H412621701, P30DK050456-18; Mayo Clinic Center for Regenerative Medicine; American Diabetes Association, Grant number: 1-16-JDF-062.
- Energy metabolism
- Histone deacetylase 3
- Insulin sensitivity
- Type 2 diabetes
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't