Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice

Binder, Elke; Bermúdez‐Silva, Francisco Javier; Elie, Melissa; Lesté-Lasserre, Thierry; Belluomo, Ilaria; Clark, Samantha; Duchampt, Adeline; Mithieux, Gilles; Cota, Daniela

doi:10.1002/oby.20578

Cited by 38 publications

(72 citation statements)

References 42 publications

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“…41–45 As a consequence, supplementation with BCAAs or a BCAA-rich diet is believed to improve metabolic health; an increase in the recommended dietary allowance for protein has been proposed, which would effectively increase dietary levels of BCAAs. 7,13,20,22,46–51 Nevertheless, the idea that BCAAs or their supplementation might have a positive role in preventing metabolic disease is controversial.…”

Section: Bcaas and Metabolic Healthmentioning

confidence: 99%

Branched-chain amino acids in metabolic signalling and insulin resistance

2014

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Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

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Section: Bcaas and Metabolic Healthmentioning

confidence: 99%

Branched-chain amino acids in metabolic signalling and insulin resistance

2014

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“…As to adipose tissue energy metabolism, leucine restriction was able to induce adipose tissue browning and raise energy expenditure with isocaloric diets in mice (71,415). Of note, leucine supplementation, but not restriction, exerted browning effects in obese models (34,35). The relevance of these studies for human physiology is uncertain.…”

Section: Specific Amino Acids and Insulin Resistancementioning

confidence: 99%

Interorgan Metabolic Crosstalk in Human Insulin Resistance

Gancheva

Jeleník

Álvarez-Hernández

et al. 2018

Physiological Reviews

154

111

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Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.

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“…However, BCAAs play a metabolic role beyond the requirements for protein synthesis [19,20]. BCAAs are not only substrates for various metabolic pathways, such lipid and glucose metabolism [21,22,23], but can also serve as signaling molecules controlling signal transduction pathways and gene transcription [21,24,25,26]. In many cases the activation of metabolic pathways is in proportion to dietary intake of amino acids [19], for example, tryptophan, which is a precursor for the appetite-modulating neurotransmitter serotonin [27,28] or leucine, which modulates glycemic control, possibly through phosphorylation of phosphatidylinositol-3 kinase [24,29,30] and regulates muscle protein synthesis via mechanistic target of rapamycin complex 1 (mTORC1) [31,32].…”

Section: Introductionmentioning

confidence: 99%

A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats

French

Dridi²,

Shouse

et al. 2017

Nutrients

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A primary factor in controlling and preventing obesity is through dietary manipulation. Diets higher in protein have been shown to improve body composition and metabolic health during weight loss. The objective of this study was to examine the effects of a high-protein diet versus a moderate-protein diet on muscle, liver and fat metabolism and glucose regulation using the obese Zucker rat. Twelve-week old, male, Zucker (fa/fa) and lean control (Fa/fa) rats were randomly assigned to either a high-protein (40% energy) or moderate-protein (20% energy) diet for 12 weeks, with a total of four groups: lean 20% protein (L20; n = 8), lean 40% protein (L40; n = 10), obese 20% protein (O20; n = 8), and obese 40% protein (O40; n = 10). At the end of 12 weeks, animals were fasted and euthanized. There was no difference in food intake between L20 and L40. O40 rats gained less weight and had lower food intake (p < 0.05) compared to O20. O40 rats had lower liver weight (p < 0.05) compared to O20. However, O40 rats had higher orexin (p < 0.05) levels compared to L20, L40 and O20. Rats in the L40 and O40 groups had less liver and muscle lipid deposition compared to L20 and L40 diet rats, respectively. O40 had decreased skeletal muscle mechanistic target of rapamycin complex 1 (mTORC1) phosphorylation and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to O20 (p < 0.05), with no difference in 5′ AMP-activated protein kinase (AMPK), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), protein kinase B (Akt) or p70 ribosomal S6 kinase (p70S6K) phosphorylation. The data suggest that high-protein diets have the potential to reduce weight gain and alter metabolism, possibly through regulation of an mTORC1-dependent pathway in skeletal muscle.

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Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice

Cited by 38 publications

References 42 publications

Branched-chain amino acids in metabolic signalling and insulin resistance

Branched-chain amino acids in metabolic signalling and insulin resistance

Interorgan Metabolic Crosstalk in Human Insulin Resistance

A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats

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