Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Yavari, Arash; Stocker, Claire J.; Ghaffari, Sahar; Wargent, Edward T.; Steeples, Violetta; Czibik, Gabor; Pintér, Katalin; Bellahcene, Mohamed; Woods, Angela; Morentin, Pablo Blanco Martínez de; Cansell, Céline; Lam, Brian Y.H.; Chuster, André; Petkevicius, Kasparas; Nguyen-Tu, Marie Sophie; Martínez-Sánchez, Aida; Pullen, Timothy J.; Oliver, Peter L.; Stockenhuber, Alexander; Nguyen, Chinh Duc; Lazdam, Merzaka; O’Dowd, Jacqueline; Harikumar, Parvathy E.; Tóth, Mónika; Beall, Craig; Kyriakou, Theodosios; Parnis, Julia; Sarma, Dhruv; Katritsis, George; Wortmann, Diana D.J.; Harper, Andrew R.; Brown, L. M.; Willows, Robin; Gandra, Silvia; Poncio, Victor; Figueiredo, Márcio Jansen de Oliveira; Qi, Nathan; Peirson, Stuart N.; McCrimmon, Rory J.; Gereben, Balázs; Tretter, László; Fekete, Csaba; Redwood, Charles; Yeo, Giles S.H.; Heisler, Lora K.; Rutter, Guy A.; Smith, Mark A.; Withers, Dominic J.; Carling, David; Sternick, Eduardo Back; Arch, Jonathan R. S.; Cawthorne, Michael A.; Watkins, Hugh; Ashrafian, Houman

doi:10.1016/j.cmet.2016.04.003

Cited by 92 publications

(92 citation statements)

References 71 publications

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“…AMPK also inactivates eukaryotic elongation factor-2 (eEF2), another important player in protein synthesis by activating eEF2 kinase. 33 In contrast to this well-established notion, both mTOR activity and S6 phosphorylation are increased in mouse models with predominant activation of γ2-AMPK 17, 34 suggesting that the AMPK effect on this pathway is dependent on the γ isoform. Here we demonstrate a distinct mechanism by which γ2-AMPK regulates protein synthesis via transient nuclear translocation and suppression of rRNA synthesis during acute stress.…”

Section: Discussionmentioning

confidence: 92%

“…Chronic activation of γ2-AMPK in the absence of stress, due to point mutations of Prkag2 gene that encodes the γ2 subunit, causes metabolic cardiomyopathy and obesity. 9–11, 17 It is not clear whether these effects are due to changes in the total AMPK activity or γ2-specific activity. Furthermore, AMPK substrates have been identified in the nucleus but the isoform-specificity of nuclear AMPK has been poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

Cao

Bojjireddy

Kim

et al. 2017

Circulation Research

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Rationale AMP-activated protein kinase (AMPK) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart but the isoform-specific function of AMPK remains unclear. Objective We sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart. Methods and Results We found that γ2 but not γ1 or γ3 subunit translocated into nucleus upon AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylated and inactivated RNA Pol I-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent down-regulation of pre-rRNA level led to attenuated ER stress and cell death. Deleting γ2-AMPK led to increases in pre-rRNA level, ER stress markers and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac specific deletion of γ2-AMPK (cKO). Although the total AMPK activity was unaltered in cKO hearts due to upregulation of γ1-AMPK, the lack of γ2-AMPK sensitizes the heart to myocardial ischemia/reperfusion (I/R) injury. The cKO failed to suppress pre-rRNA level during I/R, and showed a greater infarct size. Conversely, cardiac-specific overexpression of γ2-AMPK decreased ribosome biosynthesis and ER stress during I/R insult, and the infarct size was reduced. Conclusions The γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against I/R injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival and cardioprotection.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

Cao

Bojjireddy

Kim

et al. 2017

Circulation Research

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“…A striking feature of the mouse models is increased skeletal muscle glycogen accumulation, although no major changes in lipid metabolism were reported. A chronic gain-of-function AMPK model resulting from expression of AMPKγ2 with mutation of arginine 302 to glutamine (R302Q) was reported recently (Yavari et al., 2016). Mice with global homozygous expression of this mutation are hyperphagic, obese, and display impaired pancreatic insulin secretion (Yavari et al., 2016).…”

Section: Discussionmentioning

confidence: 98%

“…A chronic gain-of-function AMPK model resulting from expression of AMPKγ2 with mutation of arginine 302 to glutamine (R302Q) was reported recently (Yavari et al., 2016). Mice with global homozygous expression of this mutation are hyperphagic, obese, and display impaired pancreatic insulin secretion (Yavari et al., 2016). At least some of these effects appear to be mediated by changes in AMPK activity in the hypothalamus.…”

Section: Discussionmentioning

confidence: 98%

Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

et al. 2017

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SummaryAMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma).

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“…The generation of AMPKγ1 −/− mice has been previously described (10). Global AMPKγ2 −/− mice were generated by deleting the entire exon 7 of the gene encoding AMPKγ2 in R299Q knockin mice using Sox2cre-driven excision (48). Mice were maintained on a standard chow diet and 12:12-h light-dark cycle.…”

Section: Methodsmentioning

confidence: 99%

Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

Bultot

Jensen

Lai

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic α-subunit (α1 and α2) and regulatory β (β1 and β2)- and γ (γ1, γ2, γ3)-subunits, which are uniquely distributed across different cell types. There has been keen interest in developing specific and isoform-selective AMPK-activating drugs for therapeutic use and also as research tools. Moreover, establishing ways of enhancing cellular AMPK activity would be beneficial for both purposes. Here, we investigated if a recently described potent AMPK activator called 991, in combination with the commonly used activator 5-aminoimidazole-4-carboxamide riboside or contraction, further enhances AMPK activity and glucose transport in mouse skeletal muscle ex vivo. Given that the γ3-subunit is exclusively expressed in skeletal muscle and has been implicated in contraction-induced glucose transport, we measured the activity of AMPKγ3 as well as ubiquitously expressed γ1-containing complexes. We initially validated the specificity of the antibodies for the assessment of isoform-specific AMPK activity using AMPK-deficient mouse models. We observed that a low dose of 991 (5 μM) stimulated a modest or negligible activity of both γ1- and γ3-containing AMPK complexes. Strikingly, dual treatment with 991 and 5-aminoimidazole-4-carboxamide riboside or 991 and contraction profoundly enhanced AMPKγ1/γ3 complex activation and glucose transport compared with any of the single treatments. The study demonstrates the utility of a dual activator approach to achieve a greater activation of AMPK and downstream physiological responses in various cell types, including skeletal muscle.

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Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Cited by 92 publications

References 71 publications

Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

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