Chlebek Carolyn, McAndrews Casey, Aaronson Benjamin, Welhaven Hope D, Yu Kanglun, Costa Samantha N, Shaver Joseph, Silvia Sophia, DeMambro Victoria, June Ronald K, McGee-Lawrence Meghan E, Rosen Clifford J
Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME, USA.
University of New England College of Osteopathic Medicine, Biddeford, ME, USA.
bioRxiv. 2025 May 13:2025.05.09.653133. doi: 10.1101/2025.05.09.653133.
Obesity and calorie restriction each negatively affect skeletal health. Despite the negative effects of weight loss on the skeleton, obese patients are advised to lose weight via calorie restriction. Additionally, obesity and weight loss individually alter both whole-body and local metabolism. Little is known about bone quality and changes to the cortical metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would worsen bone quality in obese mice by shifting the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL6/J mice received 60% high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30% caloric restriction. Control animals received a 10% low-fat diet. Bodyweight and fat mass were increased by obesity and decreased with calorie restriction. Similarly, glucose and insulin tolerance were worsened with obesity but improved by weight loss. Compared to obesity, calorie restriction elicited more bone loss in both cortical and trabecular compartments. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. Our findings highlight the negative effects of obesity and subsequent caloric restriction on the skeleton. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models did not restore bone morphology or the cortical metabolome to control conditions.
肥胖和热量限制均会对骨骼健康产生负面影响。尽管体重减轻对骨骼有负面影响，但仍建议肥胖患者通过热量限制来减重。此外，肥胖和体重减轻分别会改变全身和局部的新陈代谢。在肥胖的临床前模型中，关于热量限制后骨质量和皮质代谢组的变化知之甚少。我们假设热量限制会通过改变皮质骨代谢组而使肥胖小鼠的骨质量恶化。为诱导肥胖，8周龄的雄性和雌性C57BL6/J小鼠接受60%的高脂饮食12周。在20至30周龄时，小鼠要么保持肥胖，要么通过30%的热量限制来减重。对照动物接受10%的低脂饮食。肥胖会使体重和脂肪量增加，而热量限制会使其降低。同样，肥胖会使葡萄糖和胰岛素耐受性变差，但体重减轻会使其改善。与肥胖相比，热量限制在皮质和小梁骨区域均引发了更多的骨质流失。体重减轻也会减少骨形成。肥胖和随后的热量限制均以性别依赖的方式改变了皮质骨代谢组。随饮食改变的代谢途径通常与氨基酸或脂肪酸代谢相关。在雄性中，体重减轻与色氨酸、酪氨酸、泛醌和脂肪酸相关途径的下调有关。在雌性中，热量限制下调了牛磺酸和亚牛磺酸代谢，但上调了嘧啶代谢、烟酸和烟酰胺代谢以及泛酸和辅酶A生物合成。我们的研究结果突出了肥胖和随后的热量限制对骨骼的负面影响。尽管全身代谢的组成部分有所改善，但肥胖临床前模型中的热量限制并未使骨形态或皮质代谢组恢复到对照状态。
