Thienopyridone Drugs Are Selective Activators of AMP-Activated Protein Kinase β1-Containing Complexes

Scott, John W.; Denderen, Bryce J. W. van; Jørgensen, Sebastian Beck; Honeyman, Jane; Steinberg, Gregory R.; Oakhill, Jonathan S.; Iseli, Tristan J.; Koay, Ann; Gooley, Paul R.; Stapleton, David; Kemp, Bruce E.

doi:10.1016/j.chembiol.2008.10.005

Cited by 223 publications

(228 citation statements)

References 37 publications

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“…Lastly, we demonstrate that ␤2 KO mice have increased susceptibility to weight gain and develop glucose intolerance and hyperinsulinemia when fed a HFD. Thus far, compounds that activate AMPK ␤1 containing complexes have been found (26,27). Our data suggest that the selective activation of ␤2-containing AMPK isoforms may increase exercise capacity and glucose uptake.…”

Section: Discussionmentioning

confidence: 89%

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Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Steinberg

O’Neill

Dzamko

et al. 2010

Journal of Biological Chemistry

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144

138

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AMP-activated protein kinase (AMPK) ␤ subunits (␤1 and ␤2) provide scaffolds for binding ␣ and ␥ subunits and contain a carbohydrate-binding module important for regulating enzyme activity. We generated C57Bl/6 mice with germline deletion of AMPK ␤2 (␤2 KO) and examined AMPK expression and activity, exercise capacity, metabolic control during muscle contractions, aminoimidazole carboxamide ribonucleotide (AICAR) sensitivity, and susceptibility to obesity-induced insulin resistance. We find that ␤2 KO mice are viable and breed normally. ␤2 KO mice had a reduction in skeletal muscle AMPK ␣1 and ␣2 expression despite up-regulation of the ␤1 isoform. Heart AMPK ␣2 expression was also reduced but this did not affect resting AMPK ␣1 or ␣2 activities. AMPK ␣1 and ␣2 activities were not changed in liver, fat, or hypothalamus. AICAR-stimulated glucose uptake but not fatty acid oxidation was impaired in ␤2 KO mice. During treadmill running ␤2 KO mice had reduced maximal and endurance exercise capacity, which was associated with lower muscle and heart AMPK activity and reduced levels of muscle and liver glycogen. Reductions in exercise capacity of ␤2 KO mice were not due to lower muscle mitochondrial content or defects in contraction-stimulated glucose uptake or fatty acid oxidation. When challenged with a high-fat diet ␤2 KO mice gained more weight and were more susceptible to the development of hyperinsulinemia and glucose intolerance. In summary these data show that deletion of AMPK ␤2 reduces AMPK activity in skeletal muscle resulting in impaired exercise capacity and the worsening of diet-induced obesity and glucose intolerance.The AMP-activated protein kinase (AMPK) 5 is an evolutionary conserved serine/threonine protein kinase that functions as a metabolic regulatory enzyme at both the intracellular and whole body level (1, 2). As a metabolic stress-sensing enzyme, AMPK is activated through phosphorylation of Thr 172 in the ␣-catalytic subunit by upstream kinases, liver kinase B1 (LKB1) and calcium/calmodulin-dependent kinase kinase in response to physiological processes that consume ATP (exercise) or inhibit ATP production (ischemia or hypoxia) (3). Following activation, AMPK acutely regulates lipid, protein, and carbohydrate metabolism through phosphorylation induced changes that alter enzyme activities by switching off ATP consuming anabolic pathways and switching on ATP generating catabolic pathways (4). In addition to these acute effects, AMPK regulates transcription factors to influence gene expression (4). Modulation of AMPK activity by hormones and cytokines adds a complex layer of regulation allowing energy supply and demand within a cell to be integrated with the energy requirements of the whole organism (5).AMPK functions as an ␣␤␥ heterotrimer where the C terminus of the ␤ isoforms (␤1 and ␤2) contains the subunit-binding sequence that is essential for binding the ␥ and ␣ subunits (6, 7). In addition to their structural role in maintaining the AMPK heterotrimer, AMPK ␤ subunits contain an evolutionary ...

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Section: Discussionmentioning

confidence: 89%

“…Recent studies have shown that activation of AMPK by the thienolpyridione class of drugs (26) depends on the ␤ subunit carbohydrate binding module and are specific for the ␤1 isoform (27). These data suggest that targeting of the ␤ subunits may be of therapeutic significance.…”

mentioning

confidence: 90%

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Steinberg

O’Neill

Dzamko

et al. 2010

Journal of Biological Chemistry

Self Cite

144

138

View full text Add to dashboard Cite

show abstract

“…To confirm that AMPK still was able to be activated in replicon cells, we treated them with three AMPK agonists. Two of the agonists, aminoimidazole carboxamide ribonucleotide (AICAR) (19) and metformin (20), have been well characterized, and the latter is used for treatment of type II diabetes; the third, thienopyridone A769662, selectively activates AMPK heterotrimers containing the β1 isoform (21). All three compounds could override the AMPK inhibition, as shown by elevated levels of AMPK T172 phosphorylation (Fig.…”

Section: Ampk Activity Is Inhibited In Hcv Subgenomic Replicon-harboringmentioning

confidence: 99%

Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

Mankouri

Tedbury

Gretton

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

127

142

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Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/ threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

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“…The first one is the compound A-79662 developed by Abbott Laboratories that belongs to the thienopyridone family. It seems a more promising selective activator of AMPK (Zhao et al 2007, Scott et al 2008, although it was shown to inhibit the function of the 26S proteasome by an AMPK-independent mechanism (Moreno et al 2008). The second compound is the thiazolidinone PT1 from the Shanghai Institute of Materia Medica (Pang et al 2008).…”

Section: Main Drugs That Are Ampk Activatorsmentioning

confidence: 99%

AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of a or b subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

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Thienopyridone Drugs Are Selective Activators of AMP-Activated Protein Kinase β1-Containing Complexes

Cited by 223 publications

References 37 publications

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

AMP-activated protein kinase pathway and bone metabolism

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