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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). Liver fat (A) assessed using MR (n = 6–7/group). 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 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 4: 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). Liver fat (A) assessed using MR (n = 6–7/group). 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 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 groups (Fig. 4A). Measures of liver fat at 5 and 10 weeks indicate progressive increases in SED mice (Fig. 4A). Liver fat was, however, reduced in gcgr+/+ RW mice (Fig. 4A). It is remarkable that this effect was abolished in gcgr−/− RW mice (Fig. 4A). Liver mass was reduced in gcgr+/+ RW mice (Fig. 4B). In agreement with MR data, liver TGs and DGs at killing were similar in SED mice. Liver TGs and DGs were reduced in gcgr+/+ RW mice, and there was again no effect of exercise in the absence of the glucagon receptor (Fig. 4C and D). Liver CEs and PLs were not different between groups (Fig. 4E 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)

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). Liver fat (A) assessed using MR (n = 6–7/group). 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 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

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

Figure 4: 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). Liver fat (A) assessed using MR (n = 6–7/group). 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 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 groups (Fig. 4A). Measures of liver fat at 5 and 10 weeks indicate progressive increases in SED mice (Fig. 4A). Liver fat was, however, reduced in gcgr+/+ RW mice (Fig. 4A). It is remarkable that this effect was abolished in gcgr−/− RW mice (Fig. 4A). Liver mass was reduced in gcgr+/+ RW mice (Fig. 4B). In agreement with MR data, liver TGs and DGs at killing were similar in SED mice. Liver TGs and DGs were reduced in gcgr+/+ RW mice, and there was again no effect of exercise in the absence of the glucagon receptor (Fig. 4C and D). Liver CEs and PLs were not different between groups (Fig. 4E 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