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

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 null (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.Nonalcoholic fatty liver (fatty liver) is a disease characterized by lipid infiltration in hepatocytes. Fatty liver is important to identify and treat because it may progress to more severe dysfunction and is linked to increased mortality (1). Fatty liver is also independently associated with obesity, type 2 diabetes, and insulin resistance and is an emerging component of metabolic syndrome (1). Studies in humans (2–5) and rodents (6–12) show that exercise positively affects fatty liver and/or measures of hepatic function in a manner partially independent of weight loss. It is unclear, however, how exercise causes such improvements. One mechanism that may underlie exercise-induced reductions in fatty liver is repeat bouts of hepatic glucagon action. Exercise stimulates a rise in hepatic glucagon action that spurs pathways that acutely fuel glucose production (13–18). Exercise-induced increases in glucagon action also provoke changes in hepatic gene expression consistent with chronically elevated fat oxidation (19).The current focus was to test whether exercise-induced reductions in high-fat diet (HFD)-induced fatty liver require hepatic glucagon action. Male C57BL/6 (BL6) mice were first fed HFD to establish a timeline for development of fatty liver. A magnetic resonance (MR) technique was also developed to perform noninvasive measures of liver fat. Mice with intact glucagon receptors (gcgr^+/+) and null littermates (gcgr^−/−) were then fed HFD to induce moderate fatty liver and subsequently housed with running wheels to promote voluntary physical activity or performed treadmill exercise to standardize the dose. Collectively, these data establish a timeline for HFD-induced fatty liver in BL6 mice and provide mechanistic detail to understand how exercise and hepatic glucagon action interact to reduce fatty liver.