Osteocyte-Specific TGFβ Signaling Mitigates Obesity-Induced Deregulated Energy Metabolism and Compromised Bone Quality

Abstract

Bone fragility associated with obesity is well recognized and is attributed to a cumulative decline in bone quality despite high BMD. Moreover, novel insights into skeletal physiology have revealed that bone-derived factors are key regulators of systemic energy balance. Despite the revelation that bone is both a target and a driver of energy metabolism, it is not entirely clear how obesity compromises the metabolic function of bone and whether deregulated energetics in bone play a causal role in declining bone quality.Transforming growth factor-beta (TGFβ), a key mediator of bone homeostasis, was recently shown by us to play a positive role in osteocytes, where its ablation (TβRIIocy-/-) compromised bone quality. TGFβ signaling has been previously implicated in etiologies of obesity and type 2 diabetes. Also, our unpublished unbiased transcriptomic analysis in TβRIIocy-/- mouse bones (osteocyte-enriched RNA) has shown that osteocytic ablation of TGFβ signaling causes profound changes in the expression of genes implicated in glucose and fatty metabolism. Together these observations led us to hypothesize that osteocytic TGFβ plays an integral role in regulating obesity impacted bone architecture and function in metabolism.Using hyperglycemia to model the metabolic milieu of obesity in vitro, we found that hyperglycemia upregulated TGFβ signaling in osteocytes. We also found that TGFβ acts similarly to hyperglycemia in reprogramming osteocyte cellular metabolism to promote glycolysis at the expense of oxidative phosphorylation. Thus, TGFβ may be a crucial mediator of hyperglycemia-induced metabolic reprogramming in osteocytes.In TβRIIocy-/- mice, inhibition of osteocyte-intrinsic TGFβ signaling reduced age-dependent weight gain and improved glycemic control relative to littermate controls. When subjected to a high-fat diet (HFD, 18 weeks), TβRIIocy-/- mice continued to be leaner, with lower food intake, and higher levels of activity and fatty acid metabolism in the liver compared to HFD fed littermate controls. This implicates osteocyte-intrinsic TGFβ signaling as a crucial regulator of systemic energy metabolism. TβRIIocy-/- mice on HFD also showed increased trabecular and cortical bone mass, increased bone mineral density, and protection against reduced bone strength compared to littermate controls on a similar diet.Overall, our study identifies a novel role for osteocytic TGFβ signaling in regulating energy metabolism and bone health in obesity.