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

Endocrinology. 2012 Nov;153(11):5394-405. doi: 10.1210/en.2012-1378. Epub 2012 Sep 25.

Abstract

Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal differentiation/survival, the regulation of food intake, and 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 use in brain-targeted BDNF conditional knockout mice (Bdnf(2lox/2lox)/93). The deletion of BDNF in the brain led to a metabolic phenotype characterized by hyperphagia, obesity, and increased abdominal white adipose tissue. 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 with control, Bdnf(2lox/2lox)/93 mice show greater trabecular bone volume (+50% for distal femur, P < 0.001; +35% for vertebral body, P < 0.001) and midfemoral 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 white adipose tissue, with no significant changes in sympathetic signaling or peripheral serotonin, associated with hyperphagia, obesity, and leptin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, White / metabolism*
  • Animals
  • Bone Density / genetics*
  • Bone and Bones / metabolism*
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Eating / genetics
  • Female
  • Hyperphagia / genetics
  • Hyperphagia / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Norepinephrine / metabolism
  • Obesity / genetics
  • Obesity / metabolism*
  • Serotonin / metabolism
  • Sex Factors
  • Uncoupling Protein 1

Substances

  • Brain-Derived Neurotrophic Factor
  • Ion Channels
  • Mitochondrial Proteins
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Serotonin
  • Norepinephrine