Hepatic energy state is regulated  by glucagon receptor signaling in mice.
The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor- null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism.
Berglund
Eric D
ED
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. berglunde@gmail.com
Lee-Young
Robert S
RS
Lustig
Daniel G
DG
Lynes
Sara E
SE
Donahue
E Patrick
EP
Camacho
Raul C
RC
Meredith
M Elizabeth
ME
Magnuson
Mark A
MA
Charron
Maureen J
MJ
Wasserman
David H
DH
D000244:Adenosine Diphosphate / Q000032:analysis; D000249:Adenosine Monophosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D004734:Energy Metabolism; D005934:Glucagon / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D018027:Receptors, Glucagon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018027:Receptors, Glucagon; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005934:Glucagon; D010729:Phosphoenolpyruvate Carboxykinase (GTP)