Mechanisms for the relationship between fat mass and bone mass

Food ingestion reduces bone turnover and these effects are at least partially mediated by endocrine mechanisms, such as adipocyte-derived hormones, including adiponectin and leptin, and it is possible that lipids act directly on bone. We therefore investigated the direct effects of adiponectin and saturated fatty acids on osteoblastic and osteoclastic cells in vitro and examined changes in gene expression using microarrays and real-time PCR. To determine the roles of adiponectin and leptin in vivo we have characterised the bone phenotypes of adiponectin-deficient mice and leptin-receptor deficient (db/db) mice by micro-computed tomography. Adiponectin was mitogenic to primary osteoblasts and markedly inhibited osteoclastogenesis through an indirect mechanism. Adiponectin downregulated the gene expression of key osteoclastogenic factors and induced interferon-related genes in bone marrow cultures. In adiponectin knock-out mice, trabecular bone volume and trabecular number were increased at 14 weeks of age, with similar trends observed at 8 and 22 weeks. Biomechanical testing showed lower bone fragility and reduced cortical hardness at 14 weeks. These results suggest that adiponectin negatively affects bone mass in vivo through secondary mechanisms not seen in vitro. On the other hand, leptin has anabolic effects on bone which were demonstrated in db/db mice that had dramatically reduced trabecular and cortical bone indices, by micro-computed tomography and biomechanical testing. The saturated fatty acids, palmitic and stearic acids, inhibited osteoclastogenesis while modestly increasing osteoblast proliferation, thus ruling out a non-specific toxic effect. Fatty acids did not change receptor activator of nuclear factor-κB ligand or osteoprotegerin expression in osteoblastic cells. However, the fatty acid binding GPR120 receptor was expressed in osteoblastic and osteoclastic cells, and the anti-osteoclastogenic effects of fatty acids were mimicked by a synthetic GPR120 agonist. Adiponectin is inversely related to fat mass in clinical studies and appears to negatively influence bone based on the findings in the knockout mouse, whilst leptin and saturated fatty acids are positively associated with fat mass and are likely to act as anabolic bone factors. These findings suggest that adiponectin, leptin and saturated lipids contribute to the positive relationship between fat mass and bone mass in humans.