Chronic Sleep Fragmentation During the Sleep Period Induces Hypothalamic Endoplasmic Reticulum Stress and PTP1b-Mediated Leptin Resistance in Male Mice
Open accessAbstract
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.
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Although there is preclinical and cross-sectional evidence suggesting that low sleep quality may be associated with impaired leptin metabolism, these associations may be weaker than for sleep duration.
“Although there is preclinical 70 and crosssectional evidence 64 suggesting that low sleep quality (i.e., high sleep fragmentation) may be associated with impaired leptin metabolism, it appears that these associations may be weaker than for sleep duration.”
From The effects of sleep disruption on metabolism, hunger, and satiety, and the influence of psychosocial stress and exercise: A narrative review (2024) · cites this paper as [70]
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- Authors
- Hakim, F., Wang, Y., Carreras, A., Hirotsu, C., Zhang, J., Peris, E., & Gozal, D.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Gozal, David
- Venue
- Sleep
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-01-01
- Volume
- 38
- Issue
- 1
- Pages
- 31-40
- ISSN
- 0161-8105 (ISSN-L)
- 1550-9109
- PMC
- PMC4262953
- OpenAlex
- W1981338699
- Cited by
- 90
- References
- 55
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 11 · 2018: 6 · 2017: 13 · 2016: 8 · 2015: 3 · 2014: 1
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- SLEEP (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000430)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- sleep fragmentation, endoplasmic reticulum stress, unfolded protein response, leptin resistance, hypothalamus, PTP1B, STAT3 phosphorylation, SOCS3, tauroursodeoxycholic acid, CHOP, dietary intake, obesity, metabolic syndrome, leptin receptor signaling
- MeSH terms
- Animals, Eating, Heterozygote, Hyperphagia, Hypothalamus, Male, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Sleep, Sleep Deprivation, Taurochenodeoxycholic Acid, Signal Transduction, Leptin, STAT3 Transcription Factor, Mice, Transcription Factor CHOP, Receptors, Leptin, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Unfolded Protein Response, Endoplasmic Reticulum Stress
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