Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis

Cell Metab. 2014 Sep 2;20(3):471-82. doi: 10.1016/j.cmet.2014.06.002. Epub 2014 Jul 10.


The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diet, High-Fat / adverse effects
  • Endoplasmic Reticulum Stress*
  • Energy Metabolism*
  • Glucose / metabolism*
  • Homeostasis
  • Insulin / metabolism
  • Leptin / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Neurons / metabolism*
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / metabolism
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism*
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Unfolded Protein Response
  • Up-Regulation
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Insulin
  • Leptin
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Pro-Opiomelanocortin
  • Glucose