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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. Liver fat assessed using MR (A). Liver mass (B) was assessed at killing. Liver lipids (C–F) were measured biochemically. Adenine nucleotides were measured using HPLC (G and I). Energy charge was calculated using [ATP + (ADP/2)/ATP + ADP + AMP] (H and J). Protein content (K) and/or expression (L) of hepatic AMPK, PPAR-α, and FGF21 were assessed using standard techniques and normalized to gcgr+/+ SED mice and/or 18S expression. *P < 0.05 compared with all other groups or as indicated. †P < 0.05 compared with measurements at week 0.
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Figure 6: 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. Liver fat assessed using MR (A). Liver mass (B) was assessed at killing. Liver lipids (C–F) were measured biochemically. Adenine nucleotides were measured using HPLC (G and I). Energy charge was calculated using [ATP + (ADP/2)/ATP + ADP + AMP] (H and J). Protein content (K) and/or expression (L) of hepatic AMPK, PPAR-α, and FGF21 were assessed using standard techniques and normalized to gcgr+/+ SED mice and/or 18S expression. *P < 0.05 compared with all other groups or as indicated. †P < 0.05 compared with measurements at week 0.

Mentions: Liver fat assessed by MR after 6 weeks of HFD was similar between genotypes (Fig. 6A). Repeat measures after 15 and 30 days of exercise indicate progressive increases in SED mice (Fig. 6A). In contrast, liver fat was reduced after 15 and 30 days in gcgr+/+ EX mice compared with SED controls and earlier measurements (Fig. 6A). As in gcgr−/− RW studies, liver fat was not reduced in gcgr−/− EX mice (Fig. 6A). Liver mass was also reduced in gcgr+/+ EX mice (Fig. 6B). Liver TGs and CEs were reduced in gcgr+/+ EX mice compared with other groups (Fig. 6C and D). Liver PLs and DGs were similar in all groups (Fig. 6E and F).


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. Liver fat assessed using MR (A). Liver mass (B) was assessed at killing. Liver lipids (C–F) were measured biochemically. Adenine nucleotides were measured using HPLC (G and I). Energy charge was calculated using [ATP + (ADP/2)/ATP + ADP + AMP] (H and J). Protein content (K) and/or expression (L) of hepatic AMPK, PPAR-α, and FGF21 were assessed using standard techniques and normalized to gcgr+/+ SED mice and/or 18S expression. *P < 0.05 compared with all other groups or as indicated. †P < 0.05 compared with measurements at week 0.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198076&req=5

Figure 6: 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. Liver fat assessed using MR (A). Liver mass (B) was assessed at killing. Liver lipids (C–F) were measured biochemically. Adenine nucleotides were measured using HPLC (G and I). Energy charge was calculated using [ATP + (ADP/2)/ATP + ADP + AMP] (H and J). Protein content (K) and/or expression (L) of hepatic AMPK, PPAR-α, and FGF21 were assessed using standard techniques and normalized to gcgr+/+ SED mice and/or 18S expression. *P < 0.05 compared with all other groups or as indicated. †P < 0.05 compared with measurements at week 0.
Mentions: Liver fat assessed by MR after 6 weeks of HFD was similar between genotypes (Fig. 6A). Repeat measures after 15 and 30 days of exercise indicate progressive increases in SED mice (Fig. 6A). In contrast, liver fat was reduced after 15 and 30 days in gcgr+/+ EX mice compared with SED controls and earlier measurements (Fig. 6A). As in gcgr−/− RW studies, liver fat was not reduced in gcgr−/− EX mice (Fig. 6A). Liver mass was also reduced in gcgr+/+ EX mice (Fig. 6B). Liver TGs and CEs were reduced in gcgr+/+ EX mice compared with other groups (Fig. 6C and D). Liver PLs and DGs were similar in all groups (Fig. 6E and F).

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