Peer-reviewedCC BY-NC 4.0Cell reports
Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis
10 affiliations
- 1Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA
- 2These authors contributed equally
- 3Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- 4Department of Pediatrics, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY 10021, USA
- 5Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
- 6Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA
- 7Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA
- 8Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
- 9Gale and Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, New York, NY 10021, USA
- 10Lead contact
Abstract
SUMMARY: Disruption of circadian glucocorticoid (GC) rhythms is associated with chronic stress and obesity, yet its metabolic signature remains poorly defined. Using a physiological mouse model, we show that the liver is largely protected from pathological steatosis despite profound obesity and hyperinsulinemia. We identify a unique redistribution of insulin resistance: rhythm disruption does not globally impair insulin action as occurs in diet-induced obesity. Instead, skeletal muscle develops severe insulin resistance while adipose and hepatic tissues remain functionally insulin responsive. This preserved sensitivity allows the adipose tissue to act as a metabolic reservoir, utilizing sustained hyperinsulinemia to sequester lipids and shield the liver from toxic fatty-acid flux. These findings reveal that GC-rhythm disruption uncouples obesity from hepatic steatosis by redistributing insulin action from skeletal muscle to adipose tissue and liver. Thus, GC-rhythm disruption and high-fat diet are independent and additive drivers of adiposity with divergent hepatic effects.
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BibTeX
@article{agas2026disrupted,
title = {{Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis}},
author = {Agnieszka Agas and Sanjeev Sharma and Anthony Narciso and Lucas Paulo Jacinto Saavedra and Jijo Wilson and Jack Lungstrum and Lucie Yammine and Anna S. Arzeno and Louise Lantier and Erin Kilkenny and Ahsan Uddin and Carolina E. Echeverria and Katherine R. Ferrick and Isaac Nathoo and Jonathan Gao and Edmund D. Kapelczak and Rashel Jacobo and Roma Patel and Tara TeSlaa and Marcus D. Goncalves and Timothy E. McGraw and Mary N. Teruel},
journal = {Cell reports},
year = {2026},
month = sep,
doi = {10.1016/j.celrep.2026.117926},
url = {https://doi.org/10.1016/j.celrep.2026.117926},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis
AU - Agnieszka Agas
AU - Sanjeev Sharma
AU - Anthony Narciso
AU - Lucas Paulo Jacinto Saavedra
AU - Jijo Wilson
AU - Jack Lungstrum
AU - Lucie Yammine
AU - Anna S. Arzeno
AU - Louise Lantier
AU - Erin Kilkenny
AU - Ahsan Uddin
AU - Carolina E. Echeverria
AU - Katherine R. Ferrick
AU - Isaac Nathoo
AU - Jonathan Gao
AU - Edmund D. Kapelczak
AU - Rashel Jacobo
AU - Roma Patel
AU - Tara TeSlaa
AU - Marcus D. Goncalves
AU - Timothy E. McGraw
AU - Mary N. Teruel
PY - 2026
DA - 2026/09/08
JO - Cell reports
DO - 10.1016/j.celrep.2026.117926
UR - https://doi.org/10.1016/j.celrep.2026.117926
AB - SUMMARY: Disruption of circadian glucocorticoid (GC) rhythms is associated with chronic stress and obesity, yet its metabolic signature remains poorly defined. Using a physiological mouse model, we show that the liver is largely protected from pathological steatosis despite profound obesity and hyperinsulinemia. We identify a unique redistribution of insulin resistance: rhythm disruption does not globally impair insulin action as occurs in diet-induced obesity. Instead, skeletal muscle develops severe insulin resistance while adipose and hepatic tissues remain functionally insulin responsive. This preserved sensitivity allows the adipose tissue to act as a metabolic reservoir, utilizing sustained hyperinsulinemia to sequester lipids and shield the liver from toxic fatty-acid flux. These findings reveal that GC-rhythm disruption uncouples obesity from hepatic steatosis by redistributing insulin action from skeletal muscle to adipose tissue and liver. Thus, GC-rhythm disruption and high-fat diet are independent and additive drivers of adiposity with divergent hepatic effects.
SN - 2211-1247
ER -