Glucagon Stimulates Fatty Acid Oxidation and Inhibits Triglyceride Synthesis in a PPARα-, p38 MAPK- and AMPK-Dependent Manner.

Longuet, Christine; Sinclair, Elaine M.; Maida, Adriano; Baggio, Laurie L.; Drucker, Daniel J.

Glucagon (gcg) levels are elevated in subjects with type 2 diabetes (T2DM), and contribute to the development of excess hepatic glucose production and hyperglycaemia. Accordingly, Gcgr antagonists are being assessed for the treatment of T2DM however, the consequences of blocking Gcgr signalling remain incompletely understood. As glucagon inhibits hepatic triglyceride (TG) secretion, and stimulates hepatic fatty acid (FA) beta oxidation and ketogenesis, we examined the role of exogenous glucagon and Gcgr signaling on hepatic lipid metabolism. Gcgr-/- mice exhibited a significant increase in hepatic TG secretion and decreased FA beta oxidation after fasting compared to wildtype littermate controls, demonstrating an essential role for the Gcgr in hepatic lipid metabolism. In primary hepatocytes prepared from Gcgr / mice, glucagon inhibited triglyceride synthesis and secretion, and stimulated FA beta oxidation. The effect of glucagon on TG synthesis was independent of PKA, but fully dependent on p38 MAPK and AMPK activation. In contrast, the inhibitory effect of glucagon on TG secretion was unaffected by inhibition of PKA, p38 MAPK or AMPK. Similarly, the stimulatory effect of glucagon on FA oxidation was eliminated in the presence of p38 MAPK inhibition. Interestingly, when FA oxidation was prevented with etomoxir, an irreversible CPT 1a inhibitor, glucagon no longer inhibited TG synthesis, but still reduced TG secretion in Gcgr / hepatocytes. Exogenous glucagon activated hepatocyte PPAR-dependent transcriptional activity in an AMPK- and p38 MAPK-dependent manner. These actions of glucagon appear to require PPARα, as the ability of glucagon to activate PPAR activity was substantially diminished in hepatocytes prepared from PPARα-/- mice. Furthermore, glucagon fails to significantly modulate TG synthesis and FA beta oxidation, in PPARα-/- hepatocytes. These findings demonstrate an essential role for glucagon in the control of hepatic lipid synthesis and secretion in a PPARα-/- dependent manner and illustrate that the pathways mediating inhibition of TG secretion by glucagon are distinct from the actions of glucagon on TG synthesis. These findings have implications for strategies directed at interruption of hepatic Gcgr signalling for the treatment of type 2 diabetes.

GLUCAGON; OXIDATION; FATTY acids; TRIGLYCERIDES; NUCLEAR receptors (Biochemistry); MITOGEN-activated protein kinases; PROTEIN kinases

Diabetes, 2007, Vol 56, pA39

0012-1797

Academic Journal