AMPK as a Therapeutic Target for Treating Metabolic Diseases

Day, Emily; Ford, Rebecca J.; Steinberg, Gregory R.

doi:10.1016/j.tem.2017.05.004

Cited by 509 publications

(441 citation statements)

References 166 publications

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“…40 It leads to the phosphorylation of key metabolic mediators and transcriptional regulators that are linked to cellular metabolism including PPARs. 40 It leads to the phosphorylation of key metabolic mediators and transcriptional regulators that are linked to cellular metabolism including PPARs.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, PEA induced PPAR-α both in vivo and in vitro model, increasing also its transcriptional coactivator PGC1α. 40 These effects are counteracted by AMPK/ ACC pathway activation: in fact, the overexpression of AMPK reduces lipogenic gene expression, liver triglycerides, and hepatic steatosis in hyperlipidemic diabetic rats 47 and reduces intracellular lipid accumulation in hepatocyte cells. Indeed, PEA modulated AMPK phosphorylation both in hypothalamus and white adipose tissue of ovariectomized rats, leading to a reduction of food intake and fat mass.…”

Section: Discussionmentioning

confidence: 99%

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Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

et al. 2019

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Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice.Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload. K E Y W O R D Sadenosine monophosphate-activated protein kinase (AMPK), high-fat diet, metabolic flexibility, mitochondrial dysfunction, oxidative stress, peroxisome proliferator-activated receptor (PPAR)-α

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

et al. 2019

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“…The activity of AMPK is decreased in adipose tissue from obese and insulin resistance subjects [90]. Since AMPK regulates several important metabolic pathways, some authors suggest that AMPK could be an important target to treat obesity, insulin resistance, type 2 diabetes and CVD [56, 91]. Since mTOR protein expression was not significantly altered, but the active form of AMPK (P-AMPK Thr 172) was increased in EAT compared to SAT it may be possible that autophagy is activated in EAT.…”

Section: Discussionmentioning

confidence: 99%

Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes

Burgeiro¹,

Fonseca²,

Espinoza³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Moreover, multiple authors (repeatedly) reviewed AMPK. In addition, there is a growing base of reviews focusing on different aspects of AMPK, such as the functions of AMPK in various tissues, or (patho-)physiological contexts (e.g., [1,2,3,4]). For AMPK novices, Hardie provides an excellent overview (e.g., [5,6,7,8]).…”

Section: About Ampk and Tak1mentioning

confidence: 99%

“…In addition, TAK1 activation originally was seen as an intracellular mediator of pro-inflammatory signals (such as TNF-α), giving rise to the development of TAK1 inhibitors for possible treatment of inflammatory disorders [32]. This prevalent view compounded scepticism about TAK1 as a genuine AMPK kinase, since reported AMPK effects are summarized to be the inverse, i.e., anti-inflammatory [3]. Therefore, the role of TAK1 as an upstream kinase of AMPK may be relevant only in certain physiological situations, or in response to specific signals.…”

Section: Is Stimulation Of Tak1 Sufficient For Activation Of Ampk?mentioning

confidence: 99%

Is TAK1 a Direct Upstream Kinase of AMPK?

Neumann

2018

IJMS

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Alongside Liver kinase B1 (LKB1) and Ca2+/Calmodulin-dependent protein kinase kinase 2 (CaMKK2), Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) has been suggested as a direct upstream kinase of AMP-activated protein kinase (AMPK). Several subsequent studies have reported on the TAK1-AMPK relationship, but the interpretation of the respective data has led to conflicting views. Therefore, to date the acceptance of TAK1 as a genuine AMPK kinase is lagging behind. This review provides with argumentation, whether or not TAK1 functions as a direct upstream kinase of AMPK. Several specific open questions that may have precluded the consensus are discussed based on available data. In brief, TAK1 can function as direct AMPK upstream kinase in specific contexts and in response to a subset of TAK1 activating stimuli. Further research is needed to define the intricate signals that are conditional for TAK1 to phosphorylate and activate AMPKα at T172.

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AMPK as a Therapeutic Target for Treating Metabolic Diseases

Cited by 509 publications

References 166 publications

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes

Is TAK1 a Direct Upstream Kinase of AMPK?

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