Background <p>Obesity-related osteoporosis is a metabolic disorder of the adipose tissue and bone caused by energy accumulation. The role of adipogenic and osteogenic differentiation and phenotypic transformation in the pathogenesis of osteoporosis and the relevant signaling mechanism are still unclear. Methods: Obesity-related osteoporotic mice were generated. Oil Red O and von Kossa staining, RT-PCR, and Western blotting were used to detect the differentiation capability of bone marrow mesenchymal stem cells (BMSCs) and the changes in related signaling pathways.</p> Results <p>High-energy states increased bone loss in ovariectomized mice, increased adipogenic differentiation, and inhibited the osteogenic differentiation of BMSCs from ovariectomized mice fed with a high-fat diet compared with those fed with a normal chow diet. The mTOR signaling pathway was activated during the adipogenic differentiation, while it did not change during the osteogenic differentiation of BMSCs from the ovariectomized group fed with a high-fat diet compared with the normal chow diet group. In vitro experiments showed that higher extracellular energy levels promoted adipogenic differentiation and inhibited osteogenic differentiation, while energy deficiency decreased adipogenic differentiation in mouse BMSCs through the mTOR signaling pathway.</p> Conclusion <p>The mTOR signaling pathway can mediate the phenotypic transformation of adipocytes and osteocytes in obesity-related osteoporotic mice.</p>