Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance

Nat Metab. 2019 May;1(5):570-583. doi: 10.1038/s42255-019-0065-4. Epub 2019 May 6.


Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism*
  • Animals
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Eye Proteins / physiology
  • Homeostasis
  • Insulin Resistance*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipid Metabolism
  • Lipogenesis / genetics
  • Lipogenesis / physiology
  • Liver / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Obesity / metabolism*
  • Receptors, Autocrine Motility Factor / genetics
  • Receptors, Autocrine Motility Factor / metabolism
  • Up-Regulation


  • Eye Proteins
  • Gpnmb protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • SREBP cleavage-activating protein
  • Amfr protein, mouse
  • Receptors, Autocrine Motility Factor