Fig. 7

Scheme summarizing the findings presented in this manuscript. Obesity commonly leads to devastating effects on many organs, including bone, and can be the prelude to developing hyperglycemia and diabetes, typically reducing bone quality, increasing fracture risk, and impairing bone regeneration. The key roles of hypoxia-inducible factor (HIF) signaling in regulating cellular metabolism and glucose uptake, angiogenesis, and bone biology and repair, suggested that HIF activation might concomitantly improve systemic glucose homeostasis and bone health and regenerative potential in the context of obesity and metabolic stress. Here, we tested this hypothesis by systemically administrating the HIF-prolyl-hydroxylase domain (PHD) inhibitor FG-4592 (Roxadustat) in mice challenged with a high-fat diet (HFD). Our findings reveal that pharmacological activation of the hypoxia signaling pathway can effectively reduce diet-induced body weight gain and peripheral fat accumulation as well as glucose intolerance, by increasing global energy expenditure. Concomitantly, the activation of HIF signaling was shown to improve bone health in obesogenic conditions by blocking excessive adipocyte accumulation in the bone marrow and safeguarding the bone vascular system, as well as enhancing metabolically compromised fracture repair. Thus, therapeutic HIF activation concomitantly alleviates both the metabolic and skeletal consequences of obesity and prediabetes in mice