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

Meghan E McGee-Lawrence1,2, Jessica L Pierce1, Kanglun Yu1

  • 1Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.

Journal of Cellular Physiology
|August 26, 2017
PubMed

Insights

Bone epigenetics regulate insulin sensitivity. Deleting Hdac3 in bone cells boosts osteoprotegerin (Opg), preventing type 2 diabetes and insulin resistance. This discovery offers new therapeutic avenues.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Bone Biology

Background:

  • Type 2 diabetes is a growing global health concern.
  • Understanding inter-system communication is key to developing new therapies.
  • Bone-derived factors influencing liver signaling may impact insulin resistance.

Purpose of the Study:

  • To investigate the role of the epigenetic regulator Hdac3 in osteoprogenitors.
  • To determine if Hdac3 deletion in bone cells affects diet-induced insulin resistance.
  • To elucidate the mechanism by which bone influences systemic insulin sensitivity.

Main Methods:

  • Utilized genetically modified mice with Hdac3 deletion in Osx1-expressing osteoprogenitors.
  • Administered a high-fat diet to induce insulin resistance.
  • Measured serum and skeletal gene expression of osteoprotegerin (Opg).
  • Assessed insulin sensitivity in Hdac3-deficient mice and controls.
  • Investigated the effect of the HDAC inhibitor vorinostat on Opg expression.

Main Results:

  • Hdac3 deletion in osteoprogenitors prevented high-fat diet-induced insulin resistance.
  • This protective effect was mediated by increased serum and skeletal Opg levels.
  • Reducing Opg levels in Hdac3-deficient mice exacerbated insulin resistance.
  • The HDAC inhibitor vorinostat increased Opg transcription and histone acetylation at the Opg locus.

Conclusions:

  • Hdac3 in osteoprogenitors plays a critical role in regulating systemic insulin sensitivity.
  • Bone-derived Opg is a key mediator linking Hdac3 activity in bone to metabolic homeostasis.
  • Targeting bone epigenetics, specifically Hdac3 and Opg, presents a novel therapeutic strategy for type 2 diabetes.
Keywords:
energy metabolismhistone deacetylase 3insulin sensitivitymellitusosteoblastosteoprotegerintype 2 diabetes

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