High-fat diet induced obesity and anti-activin receptor antibody: Effects on bone properties in mice.

Abstract

Weight-loss therapy often results in an unintended loss of muscle and bone mass. Inhibitors of the activin receptor signaling pathway, such as bimagrumab, an anti-activin receptor antibody (αActRIIA/IIB ab), are under investigation to counteract weight-loss induced muscle loss, but their skeletal effects in obesity remain unclear. This study investigates αActRIIA/IIB ab on bone in mice exposed to a high-fat diet (HFD) model of obesity or standard chow. Male C57BL/6 J mice were stratified into four groups (<i>n</i> = 10/group, standard chow or HFD for 10 weeks ± αActRIIA/IIB ab). αActRIIA/IIB ab (10 mg/kg) was administered twice weekly during the final three weeks. The femur and vertebral body were assessed using DEXA, μCT, mechanical testing, and histomorphometry. HFD did not affect bone density, microstructure, or strength but reduced histological bone formation markers. In standard chow mice, αActRIIA/IIB ab increased trabecular bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD) by 36 %. In HFD mice, the effect of αActRIIA/IIB ab was less pronounced but still increased BV/TV (+16 %) and vBMD (+13 %). For cortical bone, μCT parameters remained largely unaffected by αActRIIA/IIB ab, while the treatment increased periosteal mineralizing bone surfaces in standard chow mice (+217 %), but not in HFD mice. αActRIIA/IIB ab enhanced trabecular bone properties in standard chow-fed mice, but its anabolic effects were blunted in HFD-fed mice. Furthermore, αActRIIA/IIB ab improved cortical histological bone formation markers, while morphology remained unaffected, suggesting a site- or time-specific difference. Thus, αActRIIA/IIB ab holds potential for mitigating weight-loss-associated bone deterioration.