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

The nuclear receptor peroxisome proliferator activated receptor-gamma ( PPAR gamma) 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 PPAR gamma 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 PPAR gamma. 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 PPAR gamma 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.