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Updated: Apr 17, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Conditional deletion of Hdac3 in osteoprogenitor cells attenuates diet-induced systemic metabolic dysfunction
Meghan E McGee-Lawrence1, Thomas A White1, Nathan K LeBrasseur1
1Mayo Clinic, Rochester, MN, United States.
Abstract:
Obesity is a major health epidemic in the United States and a leading cause of preventable diseases including type 2 diabetes. A growing body of evidence indicates that the skeleton influences whole body metabolism and suggests a new avenue for developing novel therapeutic agents, but the underlying mechanisms are not well understood. Here, it is demonstrated that conditional deletion of an epigenetic regulator, Hdac3, in osteoblast progenitor cells abrogates high fat diet-induced insulin resistance and hepatic steatosis. These Hdac3-deficient mice have reduced bone formation and lower circulating levels of total and undercarboxylated osteocalcin, coupled with decreased bone resorption activity. They also maintain lower body fat and fasting glucose levels on normal and high fat chow diets. The mechanisms by which Hdac3 controls systemic energy homeostasis from within osteoblasts have not yet been fully realized, but the current study suggests that it does not involve elevated levels of circulating osteocalcin. Thus, Hdac3 is a new player in the emerging paradigm that the skeleton influences systemic energy metabolism.
Insights
Deleting Hdac3 in bone cells prevents obesity-related insulin resistance and fatty liver disease. This epigenetic regulator impacts whole-body metabolism, offering new therapeutic targets for metabolic disorders.
Area of Science:
- Bone biology
- Metabolic disease research
- Epigenetics
Background:
- Obesity and type 2 diabetes are significant health issues.
- The skeleton's role in whole-body metabolism is an emerging area of research.
- Understanding the mechanisms linking bone and metabolism is crucial for developing new therapies.
Purpose of the Study:
- To investigate the role of Hdac3, an epigenetic regulator, in osteoblast progenitor cells.
- To determine if Hdac3 deletion in these cells affects diet-induced metabolic dysfunction.
- To explore the skeletal and systemic metabolic consequences of Hdac3 deficiency in bone.
Main Methods:
- Conditional deletion of Hdac3 in osteoblast progenitor cells in mice.
- Assessment of metabolic parameters including insulin resistance, hepatic steatosis, body fat, and glucose levels.
- Analysis of bone formation, resorption, and circulating osteocalcin levels.
Main Results:
- Hdac3 deletion in osteoblast progenitors prevented high-fat diet-induced insulin resistance and hepatic steatosis.
- These mice exhibited reduced bone formation and resorption.
- Mice with Hdac3-deficient bone cells maintained lower body fat and fasting glucose levels.
- The protective effects did not appear to be mediated by increased circulating osteocalcin.
Conclusions:
- Hdac3 in osteoblast progenitor cells plays a critical role in regulating systemic energy homeostasis.
- Targeting Hdac3 in bone may offer a novel therapeutic strategy for obesity and related metabolic diseases.
- This study highlights the skeleton as an important endocrine organ influencing whole-body metabolism.
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