Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans

Banerjee, Jheelam; Bruckbauer, Antje; Zemel, Michael B.

doi:10.1016/j.metabol.2016.06.011

Cited by 70 publications

(55 citation statements)

References 48 publications

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“…and mitochondrial biogenesis and regulates fatty acid oxidation via the phosphorylation of ACC and the expression of Sirt1 [34]. Sirt1 is another downstream regulator of glucose and lipid metabolism that is known to improve insulin sensitivity and to stimulate mitochondrial biogenesis in skeletal muscle via interaction with AMPK/PGC1α [35].…”

Section: Discussionmentioning

confidence: 99%

Effects of Rhizome Extract of <em>Dioscorea Batatas </em>and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes

Nan¹,

Kang²,

Park³

et al. 2018

Preprint

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The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese Yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and the extract was analyzed by HPLC. The expression of C2C12 myotubes differentiation and mitochondrial biogenesis regulators were determined by reverse transcriptase (RT)-PCR or Western blot. The glucose levels and total ATP contents were determined by glucose consumption, glucose uptake and ATP assays, respectively.

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Section: Discussionmentioning

confidence: 99%

Effects of Rhizome Extract of <em>Dioscorea Batatas </em>and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes

Nan¹,

Kang²,

Park³

et al. 2018

Preprint

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“…5 Liver kinase B1 (LKB1) is an AMP-activated kinase that activates AMPK through phosphorylation of the alpha subunit of AMPK. 6 The activity of LKB1 is regulated by SIRT1 (sirtuin 1), a member of the sirtuin (NAD-dependent deacetylase) family. 7 Activation of SIRT1 leads to deacetylation and activation of LKB1 that increases AMPK phosphorylation and activity.…”

mentioning

confidence: 99%

“…AMPK can act as an upstream enzyme to stimulate SIRT1 activity through modulation of intracellular NAD þ concentration. 6 Sestrin 2 is another protein that forms a complex with AMPK and LKB1. 8 Knockout of Sestrin 2 leads to decreased AMPK activation and enhanced ischaemic injury.…”

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confidence: 99%

“…Interestingly, a recent study showed that metformin-leucine cotreatment can activate both AMPK and SIRT1. 6 Addition of leucine to metformin increases the effect of metformin on insulin sensitivity and glycemic control in that both AMPK and SIRT1 contribute to the regulation of glucose and lipid metabolism. Metformin is the most commonly prescribed drug for the treatment of Type 2 diabetes.…”

mentioning

confidence: 99%

“…12,13 Co-treatment of metformin-leucine improves insulin sensitivity and improves glucose metabolism. 6 Does metformin-leucine co-treatment provide better protection in aged hearts following IR compared with individual AMPK activation or SIRT1 activation? Clearly, this study which identifies the mechanisms of AMPK deficiency in aged hearts provides guidance to develop potential pharmacological approaches to decrease cardiac injury and subsequent heart failure development in aged hearts.…”

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confidence: 99%

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A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1

Chen

Lesnefsky

2018

Cardiovascular Research

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This editorial refers to 'Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury' by L. Wang et al., Myocardial injury is increased in aged hearts during ischaemia-reperfusion (IR) and accelerates the transition to post-infarct heart failure. 1Although many therapeutic interventions can effectively decrease cardiac injury in younger adult hearts, strategies to decrease cardiac injury in aged hearts are still limited.1 Therefore, understanding the mechanisms of injury in the aged heart during IR is critical to develop potential strategies to protect the high-risk aged heart. 2The impairment of substrate flexibility (balance between glucose usage and fatty acid oxidation) contributes to cardiac injury during IR as well as heart failure development.3 Limitation of glucose utilization and oxidation with concomitant increased fatty acid oxidation during reperfusion enhances cardiac injury. 3 Dr Li et al. found that the substrate flexibility was markedly impaired in aged hearts following IR compared with young hearts. 4 They further found that the decreased substrate flexibility was due in part to impairment of the AMPK (AMP-activated protein kinase) signalling pathway activation. Glucose uptake and utilization was decreased in parallel with enhanced fatty acid oxidation. 4 AMPK contributes an essential role in the regulation of glucose and lipid metabolism. Activation of the AMPK leads to increased glucose uptake and enhances insulin sensitivity. 5 Liver kinase B1 (LKB1) is an AMP-activated kinase that activates AMPK through phosphorylation of the alpha subunit of AMPK. 6The activity of LKB1 is regulated by SIRT1 (sirtuin 1), a member of the sirtuin (NAD-dependent deacetylase) family. 7 Activation of SIRT1 leads to deacetylation and activation of LKB1 that increases AMPK phosphorylation and activity. Thus, SIRT1-dependent activation of LKB1 stimulates AMPK activity. Dr Li's study clearly showed that the impaired AMPK activation in aged hearts was at least in part due to decreased SIRT1 activity.

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Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

Johnson

Gannon

Schnuck

et al. 2018

Lipids

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Branched‐chain amino acids (BCAA) such as leucine stimulate favorable metabolic processes involved in lean tissue preservation and skeletal muscle metabolism. However, higher levels of circulating BCAA correlate with severity of metabolic disease (including diabetes/insulin resistance), and may result from dysregulated BCAA catabolism. Past observations have demonstrated potential interaction between BCAA and dietary fat; however, much of this relationship remains underexplored. This study investigated the effect of leucine both with and without palmitate on oxidative and glycolytic metabolism, as well as indicators of BCAA catabolism using cultured skeletal muscle cells. Specifically, C2C12 myotubes were treated with or without varying concentrations of leucine both with and without palmitate for 24 h. Leucine treatment significantly elevated mRNA expression of metabolic regulators including peroxisome proliferator‐activated receptor‐gamma coactivator 1‐alpha versus leucine with concurrent palmitate treatment. Interestingly, leucine‐only, palmitate‐only, and leucine with palmitate all significantly increased cellular lipid content, which translated into significantly increased oxidative capacity under substrate‐limited conditions. However, upon the addition of excess substrate and carnitine, discrepancies in peak metabolic capacities between various treatments were no longer observed, suggesting leucine, palmitate, or the combination thereof causes a shift in metabolic preference from glycolytic to oxidative. These data also suggest leucine's effect on mitochondrial metabolism may result in part from increased lipid stores in addition to other previously documented pathways.

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Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans

Cited by 70 publications

References 48 publications

Effects of Rhizome Extract of <em>Dioscorea Batatas </em>and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes

Effects of Rhizome Extract of <em>Dioscorea Batatas </em>and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes

A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1

Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

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