Rats with high aerobic capacity display enhanced transcriptional adaptability and upregulation of bile acid metabolism in response to an acute high-fat diet

Harrison D. Stierwalt, E. Matthew Morris, Adrianna Maurer, Udayan Apte, Kathryn Phillips, Tiangang Li, Grace M.E. Meers, Lauren G. Koch, Steven L. Britton, Greg Graf, R. Scott Rector, Kelly Mercer, Kartik Shankar, John P. Thyfault

Research output: Contribution to journalArticlepeer-review


Rats selectively bred for the high intrinsic aerobic capacity runner (HCR) or low aerobic capacity runner (LCR) show pronounced differences in susceptibility for high-fat/high sucrose (HFHS) diet-induced hepatic steatosis and insulin resistance, replicating the protective effect of high aerobic capacity in humans. We have previously shown multiple systemic differences in energy and substrate metabolism that impacts steatosis between HCR and LCR rats. This study aimed to investigate hepatic-specific mechanisms of action via changes in gene transcription. Livers of HCR rats had a greater number of genes that significantly changed in response to 3-day HFHS compared with LCR rats (171 vs. 75 genes: >1.5-fold, p < 0.05). HCR and LCR rats displayed numerous baseline differences in gene expression while on a low-fat control diet (CON). A 3-day HFHS diet resulted in greater expression of genes involved in the conversion of excess acetyl-CoA to cholesterol and bile acid (BA) synthesis compared with the CON diet in HCR, but not LCR rats. These results were associated with higher fecal BA loss and lower serum BA concentrations in HCR rats. Exercise studies in rats and mice also revealed higher hepatic expression of cholesterol and BA synthesis genes. Overall, these results suggest that high aerobic capacity and exercise are associated with upregulated BA synthesis paired with greater fecal excretion of cholesterol and BA, an effect that may play a role in protection against hepatic steatosis in rodents.

Original languageEnglish
Article numbere15405
JournalPhysiological Reports
Issue number15
StatePublished - Aug 2022

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (NIH) (grant nos. DK088940‐01A1 [J.P.T.], R01DK121497 [J.P.T.], 5T32AR48523‐8 [E.M.M.], and F32DK130244 [H.D.S.]), the American Heart Association (AHA) (grant no. 14POST20110034 [E.M.M.]), and a VA Merit Grant. The HCR/LCR rat models were funded by the Office of Research Infrastructure Programs/OD Grant P40OD021331 from the NIH (L.G. Koch and S.L. Britton). H.D. Stierwalt is supported by F32DK130244 from the NIH, R.S. Rector is supported by VA Merit (grant no. I01BX003271), and J.P. Thyfault is supported by VA Merit (grant no. 1I01BX002567‐05) along with NIH grants R01DK121497, R01AR071263, and 1R01AG069781. This work was supported by resources and the use of facilities at the Harry S. Truman Memorial VA Hospital in Columbia, MO. Contact L.G.K. (Lauren.Koch2@UToledo.Edu) or S.L.B. ( brittons@umich.edu ) for information on the LCR and HCR rats: these rat models are maintained as a research resource at the University of Toledo, Toledo, Ohio.

Publisher Copyright:
© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.


  • aerobic capacity
  • bile acids
  • cholesterol
  • fatty liver

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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