FGF21, not GCN2, contributes to cortical bone remodeling due to protein and methionine restriction

Background Restriction of dietary protein/methionine is developing as an alternative approach to treat obesity and glucose intolerance due to increased levels of fibroblast growth factor 21 (FGF21). The study aimed to evaluate these dietary restrictions on bone microarchitecture in lean and obese mice, and to clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase influence the effect of dietary protein restriction on bone.

Methods Adult wild-type (WT), Fgf21-KO, and Gcn2-KO mice were fed a normal-protein (18kcal%; CON) or low-protein (4kcal%; LP) diet for 2 (not Gcn2-KO) or 27 weeks. New Zealand obese (NZO) mice were fed high-fat diets (protein, 16kcal%) providing methionine at control (0.86%) or low levels (0.17%) for 9 weeks. Long bones from the hind limbs were collected and analyzed by micro-computed tomography in view of changes in trabecular and cortical architecture.

Results In WT mice, LP feeding increased circulating FGF21 levels and cortical bone porosity, and reduced cortical thickness, area, and polar moment of inertia significantly in comparison to the CON diet in the long-term. In Fgf21-KO mice, but not in Gcn2-KO mice with elevated plasma FGF21 levels on the LP diet, all these effects were absent. Bone morphology changes did not occur after a 2-weeks dietary protein restriction. In NZO mice, methionine restriction led to a higher bone fragility under high-fat diet conditions when FGF21 was increased in the circulation.

Conclusion The reduction in bone microarchitecture following long-term dietary protein/methionine restriction appears to be mediated by FGF21 in the cortical bone.

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Publication History

Article published online:
06 May 2021