ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/jci.insight.177997
1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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1Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
2Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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Published May 23, 2024 - More info
Caloric restriction improves metabolic health, but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. P1NP, a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy X-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting-dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine — which surged after 3 days of fasting — impacted markers of osteoblast cell state in a concentration dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative anti-bone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.