Nicotine-induced Activation of AMP-activated Protein Kinase Inhibits Fatty Acid Synthase in 3T3L1 Adipocytes

An, Zhibo; Wang, Hong; Song, Ping; Zhang, Miao; Geng, Xiwen; Zou, Ming‐Hui

doi:10.1074/jbc.m703701200

Cited by 92 publications

(68 citation statements)

References 47 publications

(61 reference statements)

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“…-Earlier studies by our group and others (21,22) had established that phosphorylation of AMPK at Thr-172 correlates with AMPK activity. SNP is well characterized as an NO-releasing compound.…”

Section: Snp Increases the Level Of Ampk Thr-172 Phosphorylation And mentioning

confidence: 99%

Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells

Zhang

Xie

Dong

et al. 2008

Journal of Biological Chemistry

Self Cite

105

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2؉ chelator, indicating that NO-induced AMPK activation is guanylyl cyclase-mediated and calcium-dependent. Exposure of HUVECs or isolated mice aortas to either calcium ionophore A23187 or bradykinin significantly increased AMPK Thr-172 phosphorylation, which was abolished by N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Finally, A23187-or bradykinin-enhanced AMPK activation was significantly greater in aortas from wild type mice than those in the aortas of endothelial nitric oxide synthase knock-out mice. Taken together, we conclude that NO might act as an endogenous AMPK activator.The AMP-activated protein kinase (AMPK) 2 is a key enzyme in an important energy-sensing/signaling system by which cells sense and decode changes in energy status. The overall effect of AMPK activation is to switch off ATP-consuming pathways such as lipogenesis or gluconeogenesis, whereas switching on ATP-producing pathways such as fatty acid and glucose oxidation. AMPK is a protein consisting of three subunits designated ␣, ␤, and ␥. The ␣ subunit is the catalytic subunit containing the kinase domain, which transfers a phosphate from ATP to the target protein. The ␤ and ␥ subunits are considered regulatory components (1-3). All three subunits are required for expression of full activity (4).Phosphorylation of Thr-172 on the ␣ subunit by upstream kinases, AMPK kinases, results in AMPK activation. Several upstream kinases have been identified, including a complex of the tumor suppressor protein LKB1 and two accessory subunits, termed STRAD and MO25 (5, 6), and Ca 2ϩ /calmodulindependent protein kinase kinase (CaMKK), especially the CaMKK ␤ isoform (7-9). AMP also allosterically promotes phosphorylation at Thr-172 by LKB1 (10, 11). Any situation that causes an increase in cytoplasmic Ca 2ϩ will create a subsequent demand for ATP because Ca 2ϩ is immediately pumped out of the cytoplasm using ATP-driven pumps in the plasma membrane and endoplasmic reticulum. Activation of AMPK under these circumstances may represent a mechanism to anticipate the demand for ATP created by Ca 2ϩ entry. Nitric oxide (NO) is a small, highly reactive, diffusible free radical that has been implicated in many physiological and pathophysiological processes. NO exerts its effects through many ways including activation of the cGMP/protein kinase G pathway and through S-nitrosylation of proteins (12). There is an emerging body of evidence indicating a relationship between NO and AMPK expression/activity in cells (13). Such a relationship cooperatively promotes glucose and fatty acid oxidation. There is ample evidence showing that AMPK regulates NO production in cells. For example, endothelial nitric oxide synthase (eNOS) is phosphorylated by AMPK at position Ser-*

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Section: Snp Increases the Level Of Ampk Thr-172 Phosphorylation And mentioning

confidence: 99%

Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells

Zhang

Xie

Dong

et al. 2008

Journal of Biological Chemistry

Self Cite

105

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“…Another means by which AMPK could restrain energy depletion in adipocytes is by reducing lipolysis. In keeping with this notion, most studies suggest that AMPK acts as an anti-lipolytic signal (33,70,71,74,78,79), possibly by phosphorylating and inhibiting hormone-sensitive lipase (70), although others have found it is prolipolytic (24,29) or may not alter lipolysis (73,79). In this study, the inhibition of AMPK by compound C induced a 30% increase in lipolysis over 20 h under base-line conditions but did not affect its stimulation by isoproterenol (Fig.…”

Section: Discussionsupporting

confidence: 50%

“…This concept has been well illustrated in muscle and liver; however, its applicability to the adipocyte has been less explored (70). Some reports suggest that AMPK inhibits lipid (71)(72)(73) and protein synthesis (74) in adipocytes as it does in other cells. Its effects on glucose transport and fatty acid oxidation in the adipocyte are less clear (72,(75)(76)(77).…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

229

207

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AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis. AMP-activated protein kinase (AMPK)2 is a sensor of cellular energy state that responds to metabolic stresses and other regulatory signals. The mechanism of activation of AMPK is a complex phenomenon and is still not fully understood, although it is recognized that it involves phosphorylation of the critical Thr-172 residue of its ␣ catalytic subunit by upstream kinases such as LKB1, Ca 2ϩ -calmodulin-dependent protein kinase kinase, and possibly Tak1, a member of the mitogenactivated protein kinase kinase kinase family (1-5). AMPK is also regulated by AMP allosterically and the current view is that this both increases AMPK activity directly and makes it a poorer substrate for phosphatases (6).The role and regulation of AMPK in muscle, liver, and various cultured cells have been extensively studied. It is now well established that energy depletion because of starvation, hypoxia, and exercise increases the intracellular AMP:ATP ratio and secondarily AMPK activity (7). Upon its activation, a major role of AMPK is to replete cellular energy stores by stimulating processes that generate ATP, such as fatty acid oxidation, and inhibiting ATP-consuming pathways (e.g. lipogenesis, triglyceride synthesis, and gluconeogenesis) that are not acutel...

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“…This signaling pathway might be predominant under resting conditions, because it allows regulation of physiological functions related to vascular homeostasis (Zhang et al, 2008). Conversely, in pathological circumstances characterized by overproduction of ONOO -, it has been reported that ONOO -activates protein kinase Cf (PKCf) (Xie et al, 2006), which, in turn, phosphorylates LKB1, leading to the activation of AMPK and the energy-restoring pathways downstream (Zou et al, 2004;An et al, 2007). Interestingly, the endothelial isoform of NO synthase (eNOS) is activated by AMPK through the phosphorylation of Ser1177 (Chen et al, 1999), indicating that AMPK is also able to regulate RNS levels by inducing NO production.…”

Section: Regulation Of Ampk By Rnsmentioning

confidence: 99%

Redox implications of AMPK-mediated signal transduction beyond energetic clues

Cardaci

Filomeni

Ciriolo

2012

Journal of Cell Science

177

154

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SummarySince the discovery of AMP-dependent protein kinase (AMPK), its fundamental role in regulating metabolic pathways and the molecular mechanism underlying the regulation of its activity by adenine nucleotides has been widely studied. AMPK is not only an energy-responsive enzyme, but it also senses redox signals. This review aims at recapitulating the recent lines of evidence that demonstrate the responsiveness of this kinase to metabolic and nitroxidative imbalance, thus providing new insights into the intimate networks of redox-based signals upstream of AMPK. In particular, we discuss its well-recognized activation downstream of mitochondrial dysfunction, debate the recent findings that AMPK is directly targeted by pro-oxidant species, and question alternative redox pathways that allow AMPK to be included into the large class of redox-sensing proteins. The possible therapeutic implications of the role of AMPK in redox-associated pathologies, such as cancer and neurodegeneration, are also discussed in light of recent advances that suggest a role for AMPK in the tuning of redox-dependent processes, such as apoptosis and autophagy.Key words: ROS, Apoptosis, Autophagy, Nitric oxide Introduction Living organisms derive energy from the breakdown of the molecular bonds of nutrients, and then convert it into the more usable forms of ATP and NADPH (see Box 1). Cell homeostasis depends on the maintenance of ATP levels, whose hydrolysis can be coupled to synthesis reactions, transport across membranes and other endoergonic processes. For this reason, cells actively synthesize ATP and have evolved molecular mechanisms aimed at counteracting even slight decreases of ATP (Hardie, 2011). The mutual regulation of the ATP-regenerating and ATP-consuming processes, however, does not depend on the concentration of this single metabolite, but is in response to the energy balance of the cell (Atkinson, 1970). Indeed, the concentration of ATP, which has been estimated to range from 1 to 10 mM, can be subjected to marked variations. Therefore, the absolute intracellular ATP concentration tightly depends on the concentration of the other adenylates (adenylate pool) and should be considered as a function of the adenylate energy charge, which, in accordance

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Nicotine-induced Activation of AMP-activated Protein Kinase Inhibits Fatty Acid Synthase in 3T3L1 Adipocytes

Cited by 92 publications

References 47 publications

Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells

Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Redox implications of AMPK-mediated signal transduction beyond energetic clues

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