Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes

Schnuck, Jamie K.; Sunderland, Kyle L.; Gannon, Nicholas P.; Kuennen, Matthew R.; Vaughan, Roger A.

doi:10.1016/j.biochi.2016.06.009

Cited by 36 publications

(42 citation statements)

References 32 publications

(59 reference statements)

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“…Interestingly, both PPARγ and PPARβ/δ have been previously implicated in the regulation of BCAA metabolism in PGC‐1α Tg mice, suggesting a role of the PPAR nuclear receptor family in BCAA metabolism. And given leucine has been linked to increased expression of PGC‐1α, PPARγ, and PPARβ/δ, it is conceivable BCAA consumption may increase BCAA metabolism/catabolism (and expression of related enzymes) . Such a hypothesis is further supported by observations linking higher protein intake to increased BCAA catabolic enzyme activity in rat skeletal muscle .…”

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 91%

“…Interestingly the same group showed a metabolite of leucine, α‐ketoisocaproic acid (α‐KIC), at 2 mM to also increase glucose uptake at 30 minutes, although not as profoundly as leucine . Not surprisingly, both glucose uptake and GLUT4 content have been increased in skeletal muscle at 180 minutes following leucine oral gavage at 1.5 g/kg in SD rats with liver cirrhosis and total content of GLUT4 was increased in C2C12 myotubes following 2 mM leucine for 24 hours . Conversely, other investigations have shown no effect of leucine on GLUT4 content in Wistar rats following 0.55 g/kg leucine oral gavage at 30 minutes .…”

Section: Molecular Effects Of Bcaasmentioning

confidence: 96%

“…While the exact mechanisms by which mTOR inhibition improves glucose uptake in rats fed BCAA‐supplemented HF diets and not rats fed HF‐only is unclear, mTOR activation was enhanced in BCAA‐supplemented groups . Given that BCAAs are known activators of mTOR (which is involved in PPARγ activity and cellular lipid uptake), it may not be surprising that leucine/BCAA treatment increases cellular lipid content which may further promote insulin resistance. In addition to increased lipid content, BCAA treatment has also been linked with increased deposition of BCAA‐metabolic by‐products including acylcarnitines, which have previously been linked to insulin resistance in humans and observed following HF‐BCAA treatment of SD rats .…”

Section: Relationship Between Circulating Bcaas and Insulin Resistancementioning

confidence: 99%

“…Interestingly, N‐(9‐fluorenylmethyloxycarbonyl)‐leucine (FMOC‐leucine, a leucine‐like metabolite) selectively activates PPARγ by acting as a ligand, which was not observed with other FMOC‐amino acid metabolites . It has previously been shown that leucine may upregulate both PPARγ and FAS protein expression in myotubes leading to elevated lipid content . BCAA treatment has also been shown to increase lipid content in cultured adipocytes .…”

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

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BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

Gannon

Schnuck

Vaughan

2018

Molecular Nutrition Food Res

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129

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Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease.

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Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 91%

Section: Molecular Effects Of Bcaasmentioning

confidence: 96%

Section: Relationship Between Circulating Bcaas and Insulin Resistancementioning

confidence: 99%

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

See 2 more Smart Citations

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

Gannon

Schnuck

Vaughan

2018

Molecular Nutrition Food Res

Self Cite

129

View full text Add to dashboard Cite

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“…Differentiation was accomplished by replacing the growth medium with DMEM supplemented with 2% FBS and 100 U/mL penicillin/streptomycin for 6–8 days as previously described (Miyake et al, ). Leucine or valine from Sigma (St. Louis, MO, USA) was dissolved in culture medium and cells were treated with either 0.5, 1.0, or 2.0 mM for 24 h similar to concentrations used in previous experiments (Liang et al, ; Schnuck et al, ; Sun and Zemel, , ). Valine was used in initial gene expression experiments described below to determine if the effects of leucine were unique, and because valine did not induce any of the target genes (data not shown), it was not used in subsequent experiments.…”

Section: Methodsmentioning

confidence: 99%

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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