Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity.
Meghan E McGee-LawrenceJessica L PierceKanglun YuNatasha R CulpepperElizabeth W BradleyJennifer J WestendorfPublished in: Journal of cellular physiology (2017)
Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone-derived 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.
Keyphrases
- high fat diet
- insulin resistance
- histone deacetylase
- nuclear factor
- type diabetes
- adipose tissue
- high fat diet induced
- gene expression
- metabolic syndrome
- skeletal muscle
- toll like receptor
- polycystic ovary syndrome
- bone loss
- dna methylation
- global health
- bone mineral density
- poor prognosis
- glycemic control
- soft tissue
- bone regeneration
- oxidative stress
- postmenopausal women
- cell proliferation
- pi k akt
- genome wide association study
- immune response
- mouse model