Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice

Sleep. 2015 Jan 1;38(1):31-40. doi: 10.5665/sleep.4320.


Background: Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction.

Methods: Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice.

Results: Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice.

Conclusions: SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target.

Keywords: endoplasmic reticulum stress; leptin resistance; sleep fragmentation.

MeSH terms

  • Animals
  • Eating
  • Endoplasmic Reticulum Stress*
  • Heterozygote
  • Hyperphagia / etiology
  • Hyperphagia / physiopathology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Hypothalamus / pathology
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Receptors, Leptin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Sleep / drug effects
  • Sleep Deprivation / complications
  • Sleep Deprivation / metabolism
  • Sleep Deprivation / physiopathology*
  • Taurochenodeoxycholic Acid / pharmacology
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / genetics
  • Unfolded Protein Response


  • Ddit3 protein, mouse
  • Leptin
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factor CHOP
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1