Epinephrine responsiveness is reduced in livers from trained mice

Area of Science:

• Metabolic regulation
• Exercise physiology
• Hormonal signaling

Background:

• The liver is central to glucose homeostasis, producing glucose endogenously via glycogenolysis and gluconeogenesis.
• Hepatic glucose production (HGP) is modulated by neural-hormonal signals, including catecholamines like epinephrine.
• The impact of exercise training on the liver's response to epinephrine remains incompletely understood.

Purpose of the Study:

• To investigate the effects of prior exercise training on epinephrine-mediated hepatic glucose production (HGP) in mice.
• To elucidate the molecular mechanisms underlying altered hepatic responses to epinephrine following exercise training.

Main Methods:

• Male C57BL/6 mice underwent 12 days of voluntary wheel running (trained) or remained sedentary.
• Mice received intraperitoneal injections of epinephrine or vehicle control on day 12.
• Blood glucose levels were measured 15 minutes post-injection; liver glycogen, protein kinase-A (PKA) substrate phosphorylation, and mRNA expression of adrenergic receptors and key metabolic enzymes were analyzed.

Main Results:

• Epinephrine elicited a greater increase in blood glucose and a more significant reduction in liver glycogen in sedentary mice compared to trained mice.
• Epinephrine-induced phosphorylation of PKA substrates and increased mRNA expression of adrenergic receptors (Adra1/2a, Adrb1) and glucose-6-phosphatase (G6pc) were attenuated in trained mice.
• Trained mice exhibited higher mRNA expression of phosphodiesterases (Pde3b, Pde4b), enzymes that degrade cAMP.

Conclusions:

• Prior exercise training diminishes the liver's sensitivity to epinephrine.
• This training-induced adaptation may contribute to glycogen sparing during exercise, potentially by enhancing cAMP degradation pathways.
• Reduced hepatic responsiveness to epinephrine could be a key mechanism for improved metabolic regulation during physical exertion.