Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression

• Published in: iScience 2023-07, Vol.26 (7), p.106999-106999, Article 106999
• Main Authors: Kim, Soohyun P., Seward, Avery H., Garcia-Diaz, Jean, Alekos, Nathalie, Gould, Nicole R., Aja, Susan, Stains, Joseph P., Wolfgang, Michael J., Riddle, Ryan C.
• Format: Article
• Language: English
• Subjects: Cell biology; Molecular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106999

The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventing bone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions. [Display omitted] •PPARγ in osteoblasts and osteocytes regulates bone and fat mass•Mice lacking PPARγ in bone have reduced sclerostin production•Sclerostin contributes to the bone and adipose phenotypes of PPARγ mutant mice•Sclerostin loss of function synergizes with PPARγ to improve metabolism Molecular physiology; Cell biology