Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

Logie, Lisa; Lees, Zoe; Allwood, J. William; McDougall, Gordon J.; Beall, Craig; Rena, Graham

doi:10.1111/dom.13455

Cited by 10 publications

(7 citation statements)

References 45 publications

(94 reference statements)

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“…Interestingly, although not significant, AICAR appears to reduce whole body mass loss and does significantly decrease circulating FFAs. Studies have shown that AICAR improves insulin sensitivity as well as glucose uptake and fat oxidation in skeletal muscle while suppressing glucose production in the liver [42], [43]. As such, while this pharmacological agent does not affect the browning of adipose, it may exert downstream benefits via modulation of hyperglycemia/insulin resistance, hallmarks of the hypermetabolic response to severe burn injury [2].…”

Section: Discussionmentioning

confidence: 99%

Metformin prevents the pathological browning of subcutaneous white adipose tissue

Auger

Knuth

Abdullahi

et al. 2019

Molecular Metabolism

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Objective Browning, the conversion of white adipose tissue (WAT) to a beige phenotype, has gained interest as a strategy to induce weight loss and improve insulin resistance in metabolic disorders. However, for hypermetabolic conditions stemming from burn trauma or cancer cachexia, browning is thought to contribute to energy wasting and supraphysiological nutritional requirements. Metformin's impact on this phenomenon and underlying mechanisms have not been explored. Methods We used both a murine burn model and human ex vivo adipose explants to assess metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)'s effects on the development of subcutaneous beige adipose. Enzymes involved in fat homeostasis and browning, as well as mitochondrial dynamics, were assessed to determine metformin's effects. Results Treatment with the biguanide metformin lowers lipolysis in beige fat by inducing protein phosphatase 2A (PP2A) independently of adenosine monophosphate kinase (AMPK) activation. Increased PP2A activity catalyzes the dephosphorylation of acetyl-CoA carboxylase (Ser 79) and hormone sensitive lipase (Ser 660), thus promoting fat storage and the “whitening” of otherwise lipolytic beige adipocytes. Moreover, co-incubation of metformin with the PP2A inhibitor okadaic acid countered the anti-lipolytic effects of this biguanide in human adipose. Additionally, we show that metformin does not activate this pathway in the WAT of control mice and that AICAR sustains the browning of white adipose, offering further evidence that metformin acts independently of this cellular energy sensor. Conclusions This work provides novel insights into the mechanistic underpinnings of metformin's therapeutic benefits and potential as an agent to reduce the lipotoxicity associated with hypermetabolism and adipose browning.

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Section: Discussionmentioning

confidence: 99%

Metformin prevents the pathological browning of subcutaneous white adipose tissue

Auger

Knuth

Abdullahi

et al. 2019

Molecular Metabolism

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“…On the other hand, this process became questionable after publication of results showing that AICAR directly inhibits fructose-1,6-bisphosphatase in hepatocytes lacking AMPK [ 29 ]. Despite contradictory results, the latest research seem to support the mutual impact of AICAR and AMPK on hepatic glucose production [ 30 ]. The second group of AMPK activators are compounds binding directly to β subunit of AMPK.…”

Section: Structure and Activation Of Ampkmentioning

confidence: 99%

The role of AMPK in metabolism and its influence on DNA damage repair

et al. 2020

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One of the most complex health disproportions in the human body is the metabolic syndrome (MetS). It can result in serious health consequences such as type 2 diabetes mellitus, atherosclerosis or insulin resistance. The center of energy regulation in human is AMP-activated protein kinase (AMPK), which modulates cells’ metabolic pathways and protects them against negative effects of metabolic stress, e.g. reactive oxygen species. Moreover, recent studies show the relationship between the AMPK activity and the regulation of DNA damage repair such as base excision repair (BER) system, which is presented in relation to the influence of MetS on human genome. Hence, AMPK is studied not only in the field of counteracting MetS but also prevention of genetic alterations and cancer development. Through understanding AMPK pathways and its role in cells with damaged DNA it might be possible to improve cell’s repair processes and develop new therapies. This review presents AMPK role in eukaryotic cells and focuses on the relationship between AMPK activity and the regulation of BER system through its main component—8-oxoguanine glycosylase (OGG1).

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“…Uridine uptake assay was performed as described [ 48 ]. Briefly, C2C12 myotubes were washed once in uridine uptake buffer (20 mM Tris–HCl, 3 mM KH 2 PO 4 , 1 mM MgCl 2 , 2 mM CaCl 2 , 5 mM glucose, 130 mM NaCl, pH 7.4) before incubating at room temperature in 400 μl uridine uptake buffer containing vehicle (0.1% DMSO), NBMPR, or SBI-0206965.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965

Ahwazi

Neopane

Markby

et al. 2021

Biochemical Journal

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SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMPK inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK-activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥ 25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.

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Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

Cited by 10 publications

References 45 publications

Metformin prevents the pathological browning of subcutaneous white adipose tissue

Metformin prevents the pathological browning of subcutaneous white adipose tissue

The role of AMPK in metabolism and its influence on DNA damage repair

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965

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