Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction

Justin A. Fletcher, Grace M. Meers, M. Harold Laughlin, Jamal A. Ibdah, John P. Thyfault, R. S. Rector

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Chronic treatment with fibroblast growth factor 21 (FGF-21) favorably improves obesity and nonalcoholic fatty liver disease (NAFLD) outcomes; however, FGF-21 expression is paradoxically elevated in obese conditions. Here, we sought to determine the effects of obesity prevention by daily exercise (EX) vs. caloric restriction (CR) on hepatic FGF-21 in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Four-week-old male OLETF rats were randomized into groups (n = 7-8 per group) of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETFEX), or CR (OLETF-CR; 70% of SED) until 40 weeks of age. Nonhyperphagic, Long-Evans Tokushima Otsuka (LETOSED) rats served as controls. Both daily EX and CR prevented obesity and NAFLD development observed in the OLETFSED animals. This was associated with significantly (p < 0.01) lower serum FGF-21 (~80% lower) and hepatic FGF-21 mRNA expression (~65% lower) in the OLETF-EX and OLETF-CR rats compared with the OLETF-SED rats. However, hepatic FGF-21 protein content was reduced to the greatest extent in the OLETF-EX animals (50% of OLETF-SED) and did not differ between the OLETF-SED and OLETF-CR rats. Hepatic FGF-21 signaling mediators - hepatic FGF-21 receptor 2 (FGFR2, mRNA expression), hepatic FGF-21 receptor substrate 2 (FRS2, protein content), and co-receptor β-Klotho (protein content) - were all elevated (60%-100%, ~40%, and +30%-50%, respectively) in the OLETF-EX and OLETF-CR animals compared with the OLETF-SED animals. Daily exercise and caloric restriction modulate hepatic FGF-21 and its primary signaling mediators in the hyperphagic OLETF rat. Enhanced metabolic action of FGF-21 may partially explain the benefits of exercise and caloric restriction on NAFLD outcomes.

Original languageEnglish (US)
Pages (from-to)1054-1062
Number of pages9
JournalApplied Physiology, Nutrition and Metabolism
Issue number6
StatePublished - Dec 2012
Externally publishedYes


  • FGF-21
  • FGFR2
  • OLETF rats
  • Obesity
  • Physical activity
  • β-klotho

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Nutrition and Dietetics
  • Physiology (medical)


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