Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice

Abstract

Li H, Xu M, Lee J, He C, Xie Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol Endocrinol Metab 303: E1234 -E1244, 2012. First published September 11, 2012; doi:10.1152/ajpendo.00198.2012.-Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementationprevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD ϩ levels, which decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) and forkhead box O1 (FoxO1). The deacetylation of PGC1␣ may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1␣ and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity. leucine supplementation; obesity; SIRT1; PGC1␣; FoxO1; insulin resistance OBESITY, THE MOST COMMON NUTRITIONAL DISORDER in Western countries, is primarily an imbalance between calorie intake and energy expenditure (17). Increasing evidence suggests that obesity and insulin resistance are associated with reduced mitochondrial biogenesis and impaired mitochondrial function (32), which can be triggered by adverse nutrition such as increased fatty acid exposure resulting from high-fat diet (HFD) or overfeeding. Impaired mitochondrial function leads to lipid accumulation in fat tissue, skeletal muscle, and liver, impairing insulin signaling and glucose metabolism (3). Interventions to increase mitochondrial biogenesis and improve mitochondrial function have been shown to correct insulin signaling and metabolic abnormalities (35).Traditionally, strategies for preventin...

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

“…Proteins were extracted from cultured cells and mouse livers as described previously (19,33,54). The lysates were resolved by sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and incubated with the appropriate specific antibody.…”

“…To examine the alteration of insulin signaling, the mice were injected intraperitoneally with insulin (0.15 U/g) or normal saline and euthanized 15 min later. Their livers were collected for Western blotting of phosphorylated Akt (33).…”

Pre-exercise casein peptide supplementation enhances endurance training-induced mitochondrial enzyme activity in slow twitch muscle, but not fast twitch muscle of high fat diet-fed mice

“…Previous studies have reported that branched-chain amino acid (BCAA: valine, leucine, isoleucine) supplementation enhanced mitochondrial biogenesis in middle-aged mice 4) . Furthermore, leucine supplementation prevented high fat diet-induced metabolic disorders by enhancing mitochondrial biogenesis 5) . Moreover, glutamine is involved in leucine incorporation into the cell [6][7] .…”

Restrição calórica e suplementação com leucina no destreinamento físico: parâmetros lipídicos e de sensibilidade à insulina no fígado

“…Embora a associação da suplementação com restrição calórica seja pouco estudada, trabalhos tem demonstrado que a leucina, bem como seus metabólitos, pode aumentar a expressão da SIRT-1, demonstrando um papel em comum entre essas duas intervenções (BRUCKBAUER; ZEMEL, 2011;PETZ;KLAUS, 2014). Considerando essa relação, Li H, et al (2012), ofertaram 1,5g de leucina/100 ml a camundongos obesos e verificaram que a leucina apresentou correlação com o aumento da expressão da SIRT-1, com a melhora da sensibilidade à insulina e a redução do estresse oxidativo nos animais alimentados com dieta hiperlipídica. Além disso, o ganho de peso observado nos animais que receberam a suplementação não foi associado ao acúmulo de gordura ectópica no fígado e nos músculos.…”

“…Eles também podem atuar na regulação do peso corporal, na homeostase glicêmica e estimular a oxidação de ácidos graxos (GARCIA-CARABALLO et al, 2013;KAINULAINEN;HULMI e KUJALA, 2013;LYNCH;ADAMS, 2014). Dentre os BCAA, a suplementação isolada com leucina tem demonstrado resultados no que condiz com a perda de peso, melhora da sensibilidade à insulina e do perfil lipídico ZEMEL, 2011;LI et al, 2012), por atuar na regulação do metabolismo e equilíbrio energético, afetando diretamente os tecidos periféricos, tais como o tecido adiposo branco (TAB), músculos e fígado. No entanto, o efeito direto da leucina na sinalização hepática e os mecanismos associados ainda não são totalmente compreendidos (BINDER et al, 2013;LU et al, 2013;PÁDUA et al, 2009;PEDROSA et al, 2010).…”