Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity

Meghan E. McGee-Lawrence, Jessica L. Pierce, Kanglun Yu, Natasha R. Culpepper, Elizabeth W. Bradley, Jennifer J. Westendorf

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2671-2680
Number of pages10
JournalJournal of Cellular Physiology
Volume233
Issue number4
DOIs
StatePublished - Apr 2018

Bibliographical note

Funding 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.

Keywords

  • Energy metabolism
  • Histone deacetylase 3
  • Insulin sensitivity
  • Mellitus
  • Osteoblast
  • Osteoprotegerin
  • Type 2 diabetes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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