Pivotal role of cAMP in the activation of liver glycogen breakdown in high-fat diet fed mice

Aims: Liver glycogen catabolism was evaluated in male Swiss mice fed a high-fat diet rich in saturated fatty acids (HFD) or normal fat diet (NFD) during one week. Main methods: Liver glycogenolysis (LG) and liver glucose production (LGP) were measured either under basal or stimulated conditions (infusion of glycogenolytic agents). Thus, isolated perfused livers from HFD and NFD mice were infused with glycogenolytic agents, i.e., glucagon, epinephrine, phenylephrine, isoproterenol, adenosine-3'5'- cyclic monophosphate (cAMP), N-6,2'-O-dibutyryl-cAMP (DB-cAMP), 8-bromoadenosine-cAMP (8-Br-cAMP) or N-6-monobutyryl-cAMP (N-6-MB-cAMP). Moreover, glycemia and liver glycogen content were measured. Key findings: Glycemia, liver glycogen content and basal rate of LGP and LG were not influenced by the HFD. However, LGP and LG were lower (p < 0.05) in HFD mice during the infusions of glucagon (1 nM), epinephrine (20 mu M) or phenylephrine (20 mu M). In contrast, the activation of LGP and LG during the infusion of isoproterenol (20 mu M) was not different (HFD vs. NFD). Because glucagon showed the most prominent response, the effect of cAMP, its intracellular mediator, on LGP and LG was investigated. cAMP (150 mu M) showed lower activation of LGP and LG in the HFD group. However, the activation of LGP and LG was not influenced by HFD whether DB-cAMP (3 mu M), 8-Br-cAMP (3 mu M) or N6-MB-cAMP (3 mu M) were used. Significance: The activation of LGP and LG depends on the intracellular availability of cAMP. It can be concluded that cAMP played a pivotal role on the activation of LG in high-fat diet fed mice. (C) 2014 Elsevier Inc. All rights reserved.