Bone is a uniquely adaptive tissue, responding to changes in body weight to ensure sufficient bone strength for weight-bearing: When whole body energy balance changes, bone must adapt to the resultant change in body weight. When energy balance is positive (weight gain/obesity), bone mass must increase, when energy balance is negative (weight loss/starvation) suppression of bone accrual contributes to energy conservation. In addition to direct responses to changes in local loading, we provide evidence that, as part of this system matching weight to bone strength, osteoblasts monitor their own energy balance. Moreover, they are capable of responding to these energy/nutrient cues by regulating bone mass, in part through control of insulin production and action.
Osteoblasts express key components of central energy monitoring circuits, Neuropeptide Y and its Y1R receptor. Loss of NPY or Y1R (modelling energy excess) increases bone mass and formation, and disrupts skeletal responses to long-term obesity. Osteoblasts also monitor nutrient flux through classic mTOR pathways. Loss of mTORC1 (modelling nutrient depravation) leads to severe reductions in bone mass.
Osteoblast-specific deletion of Y1R or Raptor (thereby disrupting mTORC1), produce marked changes in insulin secretion and glucose tolerance.
Osteoblast-specific Y1R KO and Raptor KO mice display altered secretion and circulating levels of osteoglycin (Ogn). Greater Ogn in Raptor KO was associated with improved insulin signalling and glucose tolerance, reduced bone mass and formation, with opposing changes in Y1R KO. Osteoglycin KO mice display reduced insulin secretion and activity at target organs, as well as increased bone mass and formation.
As a whole, this reveals a coordinated system whereby osteoblast can respond to energy/nutrient balance, and tune bone the prevailing bodyweight.