RANKL induces beige adipocyte differentiation in preadipocytes

Am J Physiol Endocrinol Metab. 2020 Jun 1;318(6):E866-E877. doi: 10.1152/ajpendo.00397.2019. Epub 2020 Apr 21.


The receptor activator of nuclear factor-κB (NF-κB) (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) are a triad of proteins that regulate bone metabolism, and serum OPG is considered a biomarker for cardiovascular diseases and Type 2 diabetes; however, the implications of OPG in adipose tissue metabolism remains elusive. In this study, we investigate RANK-RANKL-OPG signaling in white adipose tissue browning. Histological analysis of osteoprotegerin knockout (OPG-/-) mice showed subcutaneous white adipose tissue (sWAT) browning, resistance for high-fat diet-induced weight gain, and preserved glucose metabolism compared with wild-type (WT) mice. Stromal vascular fraction (SVF) cells from sWAT of OPG-/- mice showed multilocular morphology and higher expression of brown adipocyte marker genes compared with those from the WT group. Infusion of RANKL induced browning and elevated respiratory rates in sWAT, along with increased whole body oxygen consumption in mice measured by indirect calorimetry. Subcutaneous WAT-derived SVF and 3T3-L1 cells, but not mature white adipocytes, differentiated into beige adipose tissue in the presence of RANKL. Moreover, SVF cells, even under white adipocyte differentiation, showed multilocular lipid droplet, lower lipid content, and increased expression of beige adipocyte markers with RANKL stimulation. In this study, we show for the first time the contribution of RANKL to increase energy expenditure by inducing beige adipocyte differentiation in preadipocytes.

Keywords: OPG; RANK; RANKL; beige adipocyte; browning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes, Beige / cytology
  • Adipocytes, Beige / metabolism*
  • Adipocytes, Beige / ultrastructure
  • Adipocytes, White / cytology
  • Adipocytes, White / metabolism
  • Adipocytes, White / ultrastructure
  • Adipogenesis / genetics*
  • Adipose Tissue, Beige / cytology
  • Adipose Tissue, Beige / metabolism
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism*
  • Animals
  • Calorimetry, Indirect
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Lipid Droplets / ultrastructure
  • Mice
  • Mice, Knockout
  • Obesity / metabolism*
  • Osteoprotegerin / genetics*
  • Osteoprotegerin / metabolism
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / genetics
  • RANK Ligand / metabolism*
  • RANK Ligand / pharmacology
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Signal Transduction
  • Subcutaneous Fat / drug effects
  • Subcutaneous Fat / metabolism
  • Weight Gain / drug effects
  • Weight Gain / genetics


  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse