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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

Six-week treadmill 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. EX mice performed exercise (3 min at 10 m/min followed by 30 min at 20 m/min) 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. SED mice were placed in a nonmoving treadmill for 33 min 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. Pre- and postintervention Vo2max (A). Fat and lean mass (C and D) were measured using nuclear MR at indicated time points. Blood glucose (E) and insulin (F) were measured on blood from cut tail at indicated time points. FFAs (G), TGs (H), cholesterol (I), epinephrine (J), and norepinephrine (K) were measured using plasma taken at killing. Plasma epinephrine and norepinephrine taken from an arterial catheter before and after exhaustive treadmill exercise in chow-fed mice (L and M, respectively). *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 5: Six-week treadmill 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. EX mice performed exercise (3 min at 10 m/min followed by 30 min at 20 m/min) 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. SED mice were placed in a nonmoving treadmill for 33 min 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. Pre- and postintervention Vo2max (A). Fat and lean mass (C and D) were measured using nuclear MR at indicated time points. Blood glucose (E) and insulin (F) were measured on blood from cut tail at indicated time points. FFAs (G), TGs (H), cholesterol (I), epinephrine (J), and norepinephrine (K) were measured using plasma taken at killing. Plasma epinephrine and norepinephrine taken from an arterial catheter before and after exhaustive treadmill exercise in chow-fed mice (L and M, respectively). *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: A second cohort of gcgr+/+ and gcgr−/− littermate mice were fed HFD for 6 weeks and then performed 30 bouts of exercise over 6 weeks (5 days per week). Preintervention Vo2max was comparable between genotypes and similarly increased with training (Fig. 5A). Body weight was similar between groups after 6 weeks of HFD (Fig. 5B). Body weight increased in SED mice and was higher than EX mice in each genotype after training (Fig. 5B). Total fat mass was similar between genotypes prior to training and increased at 6 weeks in SED groups compared with initial measurements (Fig. 5C). Total fat mass was unchanged in EX mice (Fig. 5C). Total lean mass was unchanged in all groups (Fig. 5D).


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)

Six-week treadmill 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. EX mice performed exercise (3 min at 10 m/min followed by 30 min at 20 m/min) 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. SED mice were placed in a nonmoving treadmill for 33 min 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. Pre- and postintervention Vo2max (A). Fat and lean mass (C and D) were measured using nuclear MR at indicated time points. Blood glucose (E) and insulin (F) were measured on blood from cut tail at indicated time points. FFAs (G), TGs (H), cholesterol (I), epinephrine (J), and norepinephrine (K) were measured using plasma taken at killing. Plasma epinephrine and norepinephrine taken from an arterial catheter before and after exhaustive treadmill exercise in chow-fed mice (L and M, respectively). *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 5: Six-week treadmill 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. EX mice performed exercise (3 min at 10 m/min followed by 30 min at 20 m/min) 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. SED mice were placed in a nonmoving treadmill for 33 min 5 days per week for 6 weeks between 10:00 a.m. and 12:00 p.m. Pre- and postintervention Vo2max (A). Fat and lean mass (C and D) were measured using nuclear MR at indicated time points. Blood glucose (E) and insulin (F) were measured on blood from cut tail at indicated time points. FFAs (G), TGs (H), cholesterol (I), epinephrine (J), and norepinephrine (K) were measured using plasma taken at killing. Plasma epinephrine and norepinephrine taken from an arterial catheter before and after exhaustive treadmill exercise in chow-fed mice (L and M, respectively). *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: A second cohort of gcgr+/+ and gcgr−/− littermate mice were fed HFD for 6 weeks and then performed 30 bouts of exercise over 6 weeks (5 days per week). Preintervention Vo2max was comparable between genotypes and similarly increased with training (Fig. 5A). Body weight was similar between groups after 6 weeks of HFD (Fig. 5B). Body weight increased in SED mice and was higher than EX mice in each genotype after training (Fig. 5B). Total fat mass was similar between genotypes prior to training and increased at 6 weeks in SED groups compared with initial measurements (Fig. 5C). Total fat mass was unchanged in EX mice (Fig. 5C). Total lean mass was unchanged in all groups (Fig. 5D).

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