PGC-1α in hepatic UPR during high-fat high-fructose diet and exercise training in mice

Physiol Rep. 2018 Aug;6(15):e13819. doi: 10.14814/phy2.13819.


Diet-induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC-1α is a transcriptional coactivator involved in exercise training-induced adaptations in muscle and liver. Therefore, the aim of this study was to test the hypothesis that PGC-1α is required for exercise training-mediated prevention of diet-induced steatosis and UPR activation in liver. Male liver-specific PGC-1α knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high-fat high-fructose diet (HFF). After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1α phosphorylation. Exercise training prevented the HFF-induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively. Lack of PGC-1α in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet-induced hepatic triglyceride accumulation and hepatic UPR activation. In addition, PGC-1α was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC-1α in exercise training-induced adaptations in hepatic UPR.

Keywords: UPR; Exercise training; PGC-1α; high-fat diet; liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight / physiology
  • Diet, High-Fat / adverse effects*
  • Exercise Test / methods
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / prevention & control*
  • Fructose / administration & dosage*
  • Fructose / adverse effects
  • Glucose Tolerance Test
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Knockout
  • Organ Size / physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / deficiency
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / physiology*
  • Physical Conditioning, Animal / physiology*
  • Unfolded Protein Response / physiology*


  • Blood Glucose
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Fructose