Central depletion of brain-derived neurotrophic factor in mice results in high bone mass and metabolic phenotype.

Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal differentiation/survival, in the regulation of food intake, and in the pathobiology of obesity and type 2 diabetes mellitus. BDNF and its receptor are expressed in osteoblasts and chondrocyte. BDNF in vitro has a positive effect on bone; whether central BDNF affects bone mass in vivo is not known. We therefore examined bone mass and energy utilization in brain-targeted BDNF conditional knock-out mice (Bdnf2lox/2lox/93). The deletion of BDNF in the brain led to a metabolic phenotype characterized by hyperphagia, obesity and increased abdominal white adipose tissue (WAT). Central BDNF deletion produces a marked skeletal phenotype characterized by increased femur length, elevated whole bone mineral density and bone mineral content. The skeletal changes are developmentally regulated and appear concurrently with the metabolic phenotype, suggesting that the metabolic and skeletal actions of BDNF are linked. The increased bone development is evident in both the cortical and trabecular regions. Compared to control, Bdnf2lox/2lox/93 mice show greater trabecular bone volume (BV/TV +50% for distal femur, p<0.001; +35% for vertebral body, p<0.001) and mid-femoral cortical thickness (+11 to 17%, p<0.05), measured at 3 and 6 months of age. The skeletal and metabolic phenotypes were gender-dependent with female being more affected than male mice. However, uncoupling Protein-1 expression in brown fat, a marker of sympathetic tone, was not different between genotypes. We show that deletion of central BDNF expression in mice results in increased bone mass and WAT, with no significant changes in sympathetic signaling or peripheral serotonin, associated with hyperphagia, obesity and leptin resistance.