In C57BL/6J mice, weight loss in previously obese mice reduced bone mass and shifted the cortical bone metabolome

Obesity is linked to increased fracture risk. Despite the negative effects of weight loss on the skeleton, patients with obesity are advised to lose weight via calorie restriction. Obesity and weight loss individually alter both whole-body and local metabolism. Little is known about changes to bone mass and metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would reduce bone mass in obese mice and would alter the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL/6J mice received 60 % kCal high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30 % caloric restriction. Controls consumed 10 % kCal low-fat diet. Compared to obesity, calorie restriction elicited cortical bone loss and trabecular thinning. 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. In summary, despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone mass and did not restore the cortical metabolome to control conditions.