Pharmacological HIF activation protects against diet-induced obesity, glucose intolerance, and skeletal dysfunction by exerting dual beneficial effects on energy metabolism and bone.

Obesity and type-2 diabetes, two interconnected and increasingly prevalent metabolic disorders, are associated with poor bone quality, higher fracture risk, and impaired fracture repair. The causes are not yet resolved but appear to relate to the impaired glucose homeostasis, altered bone material properties and remodeling, and compromised skeletal vascularization. Each of these features is impacted by hypoxia-inducible factor (HIF) signaling, which led us to hypothesize that HIF pathway modulation might be an effective strategy to concomitantly improve energy metabolism and bone health in conditions of metabolic stress. Here, we evaluated whether pharmacological HIF activation using the HIF-prolyl-hydroxylase-domain enzyme (PHD) inhibitor FG-4592 (Roxadustat) could protect mice against the adverse skeletal and metabolic consequences of high-fat diet (HFD)-induced obesity. We found that systemic FG-4592 treatment effectively prevented HFD-triggered body weight gain, glucose intolerance, and peripheral fat accumulation, associated with globally increased energy expenditure. Concomitantly, FG-4592 administration prevented the skeletal vascular damage, marrow fat accumulation, and bone formation deficits that were caused by HFD. Moreover, the HIF-activating drug also improved glucose metabolism and bone regeneration in a model of compromised fracture repair associated with overnutrition. Specifically, short-term FG-4592 treatment during fracture recovery reduced the body weight and fat mass of obese mice, improved glucose tolerance, and enhanced the fracture bridging capacity, along with promoting callus vascularization. These findings demonstrate that systemic hypoxia signaling stimulation using PHD inhibitors alleviates both the metabolic and skeletal consequences of diet-induced obesity in mice, highlighting its potential as a dual-action therapeutic strategy for enhancing glucose homeostasis and bone health/regeneration in disorders of obesity and metabolic dysfunction.