Globular adiponectin reverses osteo-sarcopenia and altered body composition in ovariectomized rats

Bone. 2017 Dec;105:75-86. doi: 10.1016/j.bone.2017.08.005. Epub 2017 Aug 12.

Abstract

Adiponectin regulates various metabolic processes including glucose flux, lipid breakdown and insulin response. We recently reported that adiponectin receptor1 (adipoR1) activation by a small molecule reverses osteopenia in leptin receptor deficient db/db (diabetic) mice. However, the role of adiponectin in bone metabolism under the setting of post-menopausal (estrogen-deficiency) osteopenia and associated metabolic derangements has not been studied. Here, we studied the therapeutic effect of the globular form of adiponectin (gAd), which is predominantly an adipoR1 agonist, in aged ovariectomized (OVX) rats and compared it with standard-of-care anti-osteoporosis drugs. In OVX rats with established osteopenia, gAd completely restored BMD and load bearing capacity and improved bone quality. Skeletal effects of gAd were comparable to PTH (osteoanabolic) but better than alendronate (anti-catabolic). Both osteoanabolic and anti-catabolic mechanisms led to the anti-osteoporosis effect of gAd. In cultured osteoblasts and bones, gAd increased a) adipoR1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression to promote mitochondrial respiration, which likely fueled osteoblast differentiation, b) suppressed sclerostin (a wnt antagonist) in a sirtuin1-dependent manner and c) decreased receptor-activator of nuclear factor κB ligand (RANKL) to achieve its anti-catabolic effect. The OVX-induced sarcopenia and insulin resistance were also improved by gAd. We conclude that gAd has therapeutic efficacy in estrogen deficiency-induced osteoporosis, sarcopenia and insulin resistance and hold metabolic disease modifying potential in postmenopausal women.

Keywords: Adiponectin; Adiponectin receptor-1; Anti-resorptive; Osteoanabolic; Osteopenia; PGC1α; Sarcopenia; Sclerostin.

MeSH terms

  • Adenylate Kinase / metabolism
  • Adiponectin / pharmacology
  • Adiponectin / therapeutic use*
  • Animals
  • Body Composition* / drug effects
  • Bone Morphogenetic Proteins / metabolism
  • Bone Resorption / complications
  • Bone Resorption / drug therapy
  • Cell Differentiation / drug effects
  • Cell Respiration / drug effects
  • Female
  • Genetic Markers
  • Glucose Tolerance Test
  • Lumbar Vertebrae / drug effects
  • Mice, Inbred BALB C
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Osteoblasts / drug effects
  • Osteoblasts / pathology
  • Osteogenesis / drug effects
  • Ovariectomy*
  • Oxidative Phosphorylation / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Rats, Sprague-Dawley
  • Sarcopenia / complications
  • Sarcopenia / drug therapy*
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects

Substances

  • Adiponectin
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Sost protein, rat
  • Adenylate Kinase