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 (gcgr2/2) 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 gcgr2/2 mice, thus confirming the hypothesis that exercise-stimulated hepatic glucagon receptor activation is critical to re