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Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver.

Berglund ED, Lustig DG, Baheza RA, Hasenour CM, Lee-Young RS, Donahue EP, Lynes SE, Swift LL, Charron MJ, Damon BM, Wasserman DH - Diabetes (2011)

Bottom Line: Exercise is an effective intervention to treat fatty liver.Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver.These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. berglunde@gmail.com

ABSTRACT

Objective: Exercise is an effective intervention to treat fatty liver. However, the mechanism(s) that underlie exercise-induced reductions in fatty liver are unclear. Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver.

Research design and methods: C57BL/6 mice were fed high-fat diet (HFD) and assessed using magnetic resonance, biochemical, and histological techniques to establish a timeline for fatty liver development over 20 weeks. Glucagon receptor (gcgr(-/-)) and wild-type (gcgr(+/+)) littermate mice were subsequently fed HFD to provoke moderate fatty liver and then performed either 10 or 6 weeks of running wheel or treadmill exercise, respectively.

Results: Exercise reverses progression of HFD-induced fatty liver in gcgr(+/+) mice. Remarkably, such changes are absent in gcgr(-/-) mice, thus confirming the hypothesis that exercise-stimulated hepatic glucagon receptor activation is critical to reduce HFD-induced fatty liver.

Conclusions: These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.

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Related in: MedlinePlus

Ten-week running wheel exercise intervention in glucagon receptor  (gcgr−/−) and wild-type littermates (gcgr+/+). Mice were initially fed HFD for 6 weeks prior to intervention and remained on diet throughout study (n = 9–12 mice/group). Fat and lean mass (B and C) were measured using nuclear MR. Blood glucose (D), insulin (E), and leptin (F) were measured on blood from cut tail. FFAs (G), TGs (H), and cholesterol (I) were measured at killing. *P < 0.05 within a genotype or as indicated. **P < 0.05 within both genotypes. †P < 0.05 compared with measurements at week 0.
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Figure 3: Ten-week running wheel exercise intervention in glucagon receptor (gcgr−/−) and wild-type littermates (gcgr+/+). Mice were initially fed HFD for 6 weeks prior to intervention and remained on diet throughout study (n = 9–12 mice/group). Fat and lean mass (B and C) were measured using nuclear MR. Blood glucose (D), insulin (E), and leptin (F) were measured on blood from cut tail. FFAs (G), TGs (H), and cholesterol (I) were measured at killing. *P < 0.05 within a genotype or as indicated. **P < 0.05 within both genotypes. †P < 0.05 compared with measurements at week 0.

Mentions: Gcgr+/+ and gcgr−/− mice were fed HFD for 6 weeks and subsequently housed with operable (RW) or inoperable (SED) running wheels for 10 weeks. Body weights were comparable prior to introduction of running wheels (Fig. 3A). Body weight increased in all groups, and there were no differences at any time point in gcgr+/+ mice (Fig. 3A). In contrast, body weight was reduced in gcgr−/− RW mice versus SED controls between 7 and 9 weeks (Fig. 3A). Total fat mass was similar between groups prior to introduction of running wheels and increased after 8 and 10 weeks in both SED groups (Fig. 3B). Total lean mass was unchanged in all groups (Fig. 3C). There were no differences in running wheel activity (532,432 ± 71,856 and 609,659 ± 59,592 revolutions at 10 weeks in gcgr+/+ RW and gcgr−/− RW mice, respectively).


Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver.

Berglund ED, Lustig DG, Baheza RA, Hasenour CM, Lee-Young RS, Donahue EP, Lynes SE, Swift LL, Charron MJ, Damon BM, Wasserman DH - Diabetes (2011)

Ten-week running wheel exercise intervention in glucagon receptor  (gcgr−/−) and wild-type littermates (gcgr+/+). Mice were initially fed HFD for 6 weeks prior to intervention and remained on diet throughout study (n = 9–12 mice/group). Fat and lean mass (B and C) were measured using nuclear MR. Blood glucose (D), insulin (E), and leptin (F) were measured on blood from cut tail. FFAs (G), TGs (H), and cholesterol (I) were measured at killing. *P < 0.05 within a genotype or as indicated. **P < 0.05 within both genotypes. †P < 0.05 compared with measurements at week 0.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198076&req=5

Figure 3: Ten-week running wheel exercise intervention in glucagon receptor (gcgr−/−) and wild-type littermates (gcgr+/+). Mice were initially fed HFD for 6 weeks prior to intervention and remained on diet throughout study (n = 9–12 mice/group). Fat and lean mass (B and C) were measured using nuclear MR. Blood glucose (D), insulin (E), and leptin (F) were measured on blood from cut tail. FFAs (G), TGs (H), and cholesterol (I) were measured at killing. *P < 0.05 within a genotype or as indicated. **P < 0.05 within both genotypes. †P < 0.05 compared with measurements at week 0.
Mentions: Gcgr+/+ and gcgr−/− mice were fed HFD for 6 weeks and subsequently housed with operable (RW) or inoperable (SED) running wheels for 10 weeks. Body weights were comparable prior to introduction of running wheels (Fig. 3A). Body weight increased in all groups, and there were no differences at any time point in gcgr+/+ mice (Fig. 3A). In contrast, body weight was reduced in gcgr−/− RW mice versus SED controls between 7 and 9 weeks (Fig. 3A). Total fat mass was similar between groups prior to introduction of running wheels and increased after 8 and 10 weeks in both SED groups (Fig. 3B). Total lean mass was unchanged in all groups (Fig. 3C). There were no differences in running wheel activity (532,432 ± 71,856 and 609,659 ± 59,592 revolutions at 10 weeks in gcgr+/+ RW and gcgr−/− RW mice, respectively).

Bottom Line: Exercise is an effective intervention to treat fatty liver.Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver.These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. berglunde@gmail.com

ABSTRACT

Objective: Exercise is an effective intervention to treat fatty liver. However, the mechanism(s) that underlie exercise-induced reductions in fatty liver are unclear. Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver.

Research design and methods: C57BL/6 mice were fed high-fat diet (HFD) and assessed using magnetic resonance, biochemical, and histological techniques to establish a timeline for fatty liver development over 20 weeks. Glucagon receptor (gcgr(-/-)) and wild-type (gcgr(+/+)) littermate mice were subsequently fed HFD to provoke moderate fatty liver and then performed either 10 or 6 weeks of running wheel or treadmill exercise, respectively.

Results: Exercise reverses progression of HFD-induced fatty liver in gcgr(+/+) mice. Remarkably, such changes are absent in gcgr(-/-) mice, thus confirming the hypothesis that exercise-stimulated hepatic glucagon receptor activation is critical to reduce HFD-induced fatty liver.

Conclusions: These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.

Show MeSH
Related in: MedlinePlus