AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

Johanns, Manuel; Lai, Yu‐Chiang; Hsu, Mei F.; Jacobs, Roxane; Vertommen, Didier; Sande, Jacqueline Van; Dumont, Jacques Emile; Woods, Angela; Carling, David; Hue, Louis; Viollet, Benoı̂t; Foretz, Marc; Rider, Mark H.

doi:10.1038/ncomms10856

Cited by 129 publications

(120 citation statements)

References 59 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…The phosphorylation of two key PKA substrates that promote gluconeogenesis, PFK2 and IP3R, were both reduced after metformin treatment (Miller et al 2013). Moreover, a recent study has shown that hepatic AMPK can phosphorylate and activate PDE4B to suppress glucagon-mediated cAMP/PKA activation (Johanns et al 2016), suggesting that metformin inhibits hepatic PKA via multiple pathways. Another study showed that selective inactivation of NF-κB in mouse liver enhanced insulin sensitivity and suppressed hepatic gluconeogenesis also via inhibition of the cAMP/PKA/CREB pathway (Ke et al 2015).…”

Section: Camp/pka In the Livermentioning

confidence: 97%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

151

View full text Add to dashboard Cite

In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

show abstract

Section: Camp/pka In the Livermentioning

confidence: 97%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

151

View full text Add to dashboard Cite

show abstract

“…When activated, PKA can phosphorylate numerous enzymes, regulating a variety of metabolic pathways throughout the body. In skeletal muscle and liver, the activation of PKA increases glycogen breakdown (Jensen, Brennesvik, Lai, & Shepherd, ; Johanns et al, ). In the liver, PKA also stimulates gluconeogenesis through the transcriptional activation of numerous genes, including glucose‐6‐phosphatase ( G6pc ) and phosphoenolpyruvate carboxykinase ( Pepck ) (Xie et al, ).…”

Section: Introductionmentioning

confidence: 99%

Epinephrine responsiveness is reduced in livers from trained mice

et al. 2020

View full text Add to dashboard Cite

The liver is the primary metabolic organ involved in the endogenous production of glucose through glycogenolysis and gluconeogenesis. Hepatic glucose production (HGP) is increased via neural‐hormonal mechanisms such as increases in catecholamines. To date, the effects of prior exercise training on the hepatic response to epinephrine have not been fully elucidated. To examine the role of epinephrine signaling on indices of HGP in trained mice, male C57BL/6 mice were either subjected to 12 days of voluntary wheel running or remained sedentary. Epinephrine, or vehicle control, was injected intraperitoneally on day 12 prior to sacrifice with blood glucose being measured 15 min postinjection. Epinephrine caused a larger glucose response in sedentary mice and this was paralleled by a greater reduction in liver glycogen in sedentary compared to trained mice. There was a main effect of epinephrine to increase the phosphorylation of protein kinase‐A (p‐PKA) substrates in the liver, which was driven by increases in the sedentary, but not trained, mice. Similarly, epinephrine‐induced increases in the mRNA expression of hepatic adrenergic receptors (Adra1/2a, Adrb1), and glucose‐6‐phosphatase (G6pc) were greater in sedentary compared to trained mice. The mRNA expression of cAMP‐degrading enzymes phosphodiesterase 3B and 4B (Pde3b, Pde4b) was greater in trained compared to sedentary mice. Taken together, our data suggest that prior exercise training reduces the liver's response to epinephrine. This could be beneficial in the context of training‐induced glycogen sparing during exercise.

show abstract

“…Although PDE3/4 subfamilies are expressed in the liver [9,27], PDE4B is thought to be the predominant PDE responsible for hepatic cAMP degradation [8,20]. The SDH inhibitor dimethyl malonate diminished the inhibitory effect of palmitate on PDE4B expression in the hepatocytes, suggesting that succinate might be an intermediate in the action of palmitate.…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular cAMP is synthesised by adenylyl cyclase, while phosphodiesterases (PDEs) could prevent cAMP accumulation through degradation. AMP-activated protein kinase (AMPK) is shown to antagonise hepatic glucagonstimulated cAMP signalling via PDE activation [8]. By contrast, hepatic NFκB p65 activation increases cAMP accumulation by suppressing PDE3B activity, leading to an enhanced hepatic glucagon response [9].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg5 attenuates hepatic glucagon response via suppression of succinate-associated HIF-1α induction in HFD-fed mice

Xiao

Lou

et al. 2017

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Ginsenosides regulate glucose homeostasis. This study investigated the effect of ginsenoside Rg5 (Rg5) on the hepatic glucagon response, focusing on the regulation of metabolism. Methods Mice fed a high-fat diet (HFD) showed increased hepatic glucose production (HGP). We observed the effects of Rg5 on hepatic fatty acid oxidation and glucagon response. The regulation of phosphodiesterase (PDE) 4B by succinate was also investigated in hepatocytes. Results Rg5 inhibited endogenous glucose production in HFD-fed mice. Rg5 reduced cyclic AMP (cAMP) accumulation and inhibited transcriptional regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by dephosphorylation of the cAMP response element-binding transcription factor in the liver, demonstrating the inhibitory effect on hepatic glucagon response. HFD feeding increased succinate accumulation in the liver due to the reversal of succinate dehydrogenase activation and triggered hypoxiainducible factor-1α (HIF-1α) induction. Succinate prevented cAMP degradation by inactivating PDE4B, thereby increasing cAMP accumulation in response to glucagon. Knockdown of HIF-1α with small interfering RNA diminished the effect of succinate, indicating that HIF-1α was essential for succinate to inactivate PDE4B. Rg5 inhibited succinate accumulation in hepatocytes by combating fatty acid oxidation, and thus reduced cAMP accumulation by blocking succinate/HIF-1α induction. Rg5 reduced HGP as a consequence of the inhibition of the glucagon response. Conclusions/interpretation Succinate acted as a metabolic signal to enhance the hepatic glucagon response. Rg5 reduced hepatic succinate accumulation by combating fatty acid oxidation and attenuated the hepatic glucagon response by suppressing succinate/HIF-1α induction, suggesting that succinate-associated HIF-1α induction in hepatocytes might be a therapeutic target in the treatment of diabetes.

show abstract

AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

Cited by 129 publications

References 59 publications

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Epinephrine responsiveness is reduced in livers from trained mice

Ginsenoside Rg5 attenuates hepatic glucagon response via suppression of succinate-associated HIF-1α induction in HFD-fed mice

Contact Info

Product

Resources

About