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

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Abstract

Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the V _max of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.

Abstract

The diabetes drug Metformin decreases hepatic glucose production and activates AMP-activated protein kinase (AMPK). Here the authors provide evidence that AMPK activation antagonizes glucagon signalling by activating PDE4B, lowering cAMP levels and decreasing PKA activation.

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The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism.

Simon A. Hawley, Anne Gadalla, Grith Olsen … (2002)

Metformin, a drug widely used to treat type 2 diabetes, was recently shown to activate the AMP-activated protein kinase (AMPK) in intact cells and in vivo. In this study we addressed the mechanism for this effect. In intact cells, metformin stimulated phosphorylation of the key regulatory site (Thr-172) on the catalytic (alpha) subunit of AMPK. It did not affect phosphorylation of this site by either of two upstream kinases in cell-free assays, although we were able to detect an increase in upstream kinase activity in extracts of metformin-treated cells. Metformin has been reported to be an inhibitor of complex 1 of the respiratory chain, but we present evidence that activation of AMPK in two different cell types is not a consequence of depletion of cellular energy charge via this mechanism. Whereas we have not established the definitive mechanism by which metformin activates AMPK, our results show that the mechanism is different from that of the existing AMPK-activating agent, 5-aminoimidazole-4-carboxamide (AICA) riboside. Metformin therefore represents a useful new tool to study the consequences of AMPK activation in intact cells and in vivo. Our results also show that AMPK can be activated by mechanisms other than changes in the cellular AMP-to-ATP ratio.

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Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats.

Frank Duca, Clémence Côté, Brittany A Rasmussen … (2015)

Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.

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Overview of PDEs and their regulation.

Jun Kotera, K Omori (2007)

Contraction and relaxation of vascular smooth muscle and cardiac myocytes are key physiological events in the cardiovascular system. These events are regulated by second messengers, cAMP and cGMP, in response to extracellular stimulants. The strength of signal transduction is controlled by intracellular cyclic nucleotide concentrations, which are determined by a balance in production and degradation of cAMP and cGMP. Degradation of cyclic nucleotides is catalyzed by 3',5'-cyclic nucleotide phosphodiesterases (PDEs), and therefore regulation of PDEs hydrolytic activity is important for modulation of cellular functions. Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties, and sensitivity to inhibitors. PDE families contain many splice variants that mostly are unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association proteins. Each unique variant is closely related to the regulation of a specific cellular signaling. Thus, multiple PDEs function as a particular modulator of each cardiovascular function and regulate physiological homeostasis.

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Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 08 March 2016

Publication date Collection: 2016

Volume: 7

Electronic Location Identifier: 10856

Affiliations

[1 ]Université catholique de Louvain and de Duve Institute , Avenue Hippocrate, 75, 1200 Brussels, Belgium

[2 ]Faculté de Médecine, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB) , Route de Lennik, 808, 1070 Brussels, Belgium

[3 ]Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital , DuCane Road, London W12 0NN, UK

[4 ]INSERM U1016, Institut Cochin , 75014 Paris, France

[5 ]CNRS UMR8104 , 75014 Paris, France

[6 ]Université Paris Descartes, Sorbonne Paris Cité , 75014 Paris, France

Author notes

[a ] mark.rider@ 123456uclouvain.be

[*]

These authors contributed equally to this work

[†]

Present addresses: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK

[‡]

Present addresses: Graduate Institute of Sports Training, University of Taipei, No. 101, Sec. 2, Zhongcheng Road, Shilin Dist., 11153 Taipei City, Taiwan

Author information

B. Viollet http://orcid.org/0000-0002-0121-0224

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Publisher Item ID: ncomms10856

DOI: 10.1038/ncomms10856

PMC ID: 4786776

PubMed ID: 26952277

SO-VID: 0e567e8d-1e35-499b-a037-831f5b51cef5

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

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Most cited references 50

The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism.

Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats.

Overview of PDEs and their regulation.

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