BETA-OXIDATION OF ADIPOSE-DERIVED FATTY ACIDS FUEL PTH-INDUCED BONE FORMATION

The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues able to supply fuel molecules. In the case of intermittent parathyroid hormone (iPTH) treatment, a therapeutic strategy used clinically to reduce fracture risk, the increase in bone formation is preceded by a change in lipid homeostasis. The sequence of these events led us to hypothesize that fatty acid beta-oxidation is required for the anabolic actions of this therapy. In vitro, osteoblasts treated with PTH exhibited increases in oxidation of oleate, genes involved in fatty acid beta-oxidation (RNA sequencing) and in the rate of oxygen consumption. Etomoxir, an irreversible inhibitor of the rate limiting enzyme in beta-oxidation, attenuated the effect of PTH on oxygen consumption, indicating that fatty acid catabolism is key to this response. In vivo, iPTH-induced (100 μg/kg/d for six weeks) increases in trabecular bone volume were reduced by approximately 50% in mice lacking Cpt2, an obligate enzyme in beta-oxidation, in osteoblasts (Cpt2flox/flox; Ocn-Cre) when compared to control littermates. We speculated that the fatty acids necessary to fuel iPTH-induced bone formation are released from adipose tissue since acute PTH administration increased serum free fatty acids, induced the phosphorylation of hormone sensitive lipase in white adipose depots, and stimulated a rapid decrease in the respiratory exchange ratio, indicative of an increase in fatty acid oxidation. To test this hypothesis, mice lacking the PTH receptor in adipocytes (Pth1rflox/flox; AdipoQ-Cre), or mice with impaired lipolysis due to the ablation of Atgl in adipocytes (Atglflox/flox; AdipoQ-Cre) were treated with iPTH for six weeks. When compared to control littermates, iPTH-induced acquisition of bone volume was severely blunted in each mutant mouse line. Dynamic histomorphometric analysis of Pth1rflox/flox; AdipoQ-Cre and Atglflox/flox; AdipoQ-Cre mice revealed an impaired ability of iPTH to enhance the mineral apposition rate and the bone formation rate. Collectively, these data suggest that PTH’s anabolic effect requires signaling in bone as well as in fat, wherein a lipolytic response in adipose tissue liberates fatty acids that are oxidized by osteoblasts to fuel bone formation