D, L-Buthionine-(S, R)-sulfoximine recapitulates the anti-obesity effects of sulfur amino acid restriction without the associated deleterious effects on bone in male mice

Sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine, reduces obesity but also lowers bone mineral density (BMD) and increases marrow adipose tissue. Because the SAAR diet lacks cysteine, it exerts cysteine restriction (CysR), in addition to methionine restriction (MetR). We previously reported that the anti-obesity effect of the SAAR diet was exclusively due to CysR. Follow-up studies revealed that CysR decreases obesity by lowering glutathione (GSH), and that D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, recapitulates the SAAR-induced lean phenotype on a methionine-replete diet. Here, we investigated whether the detrimental effects of the SAAR diet on bone are mediated solely by CysR and whether BSO, similar to the SAAR diet, exerts deleterious effects. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (control diet, CD), 0.12% methionine (SAAR diet), SAAR diet supplemented with a GSH precursor, N-acetylcysteine (NAC) in water, and CD supplemented with BSO in water. Femurs and tibiae of SAAR mice had lower trabecular and cortical BMD, fewer osteoblasts, reduced biomechanical strength, and more marrow adipocytes than in CD mice. NAC reversed all these effects, suggesting that CysR mediates the detrimental effects of the SAAR diet on bone. Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones. Future studies should investigate mechanisms, age-at-onset, tissue-specific, and gender-specific effects of BSO on bone health. Long-term studies to establish the therapeutic efficacy and off-target effects of BSO are critical for developing it as an anti-obesity drug in humans.