Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high‐fat diet likely by promoting insulin signaling in insulin‐target tissues

Li, Xiang; Wang, Xiaolei; Li, Rui; Ma, Yan; Guo, Haijian; Hao, Liping; Yao, Ping; Liu, Liegang; Sun, Xiufa; He, Ka; Cao, Wenhong; Yang, Xuefeng

doi:10.1002/mnfr.201200311

Cited by 53 publications

(64 citation statements)

References 59 publications

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“…However, we previously reported that the same HFD protocol did not result in altered IRS-1–PI3K activity in muscle (Castorena et al 2014). Some studies have shown that long-term HFD (8 to 16 weeks) leads to increased phosphorylation of mTOR, p70S6K, and/or RPS6 in muscle of rats or mice (Le Bacquer et al 2007; Rivas et al 2009 b ), whereas another study showed that long-term HFD (24 weeks) did not alter phosphorylation of mTOR in muscles of rats (Li et al 2013). Neither HFD nor exercise altered phosphorylation of GSK3α/β in the current study, but an earlier study reported that long-term HFD (15 weeks) led to reduced GSK3α/β phosphorylation in rat muscle (Henriksen et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

Castorena

Arias

Sharma

et al. 2015

Appl. Physiol. Nutr. Metab.

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One exercise session can improve subsequent insulin-stimulated glucose uptake by skeletal muscle in healthy and insulin-resistant individuals. Our first aim was to determine whether a brief (2 weeks) high-fat diet (HFD) that caused muscle insulin resistance would activate the mammalian target of rapamycin complex 1 (mTORC1) and/or inhibitor of κB kinase/nuclear factor κB (IKK/NF-κB) pathways, which are potentially linked to induction of insulin resistance. Our second aim was to determine whether acute exercise that improved insulin-stimulated glucose uptake by muscles would attenuate activation of these pathways. We compared HFD-fed rats with rats fed a low-fat diet (LFD). Some animals from each diet group were sedentary and others were studied 3 h postexercise, when insulin-stimulated glucose uptake was increased. The results did not provide evidence that brief HFD activated either the mTORC1 (including phosphorylation of mTORSer2448, TSC2Ser939, p70S6KThr412, and RPS6Ser235/236) or the IKK/NF-κB (including abundance of IκBα or phosphorylation of NF-κBSer536, IKKα/βSer177/181, and IκBSer32) pathway in insulin-resistant muscles. Exercise did not oppose the activation of either pathway, as evidenced by no attenuation of phosphorylation of key proteins in the IKK/NF-κB pathway (NF-κBSer536, IKKα/βSer177/181, and IκBSer32), unaltered IκBα abundance, and no attenuation of phosphorylation of key proteins in the mTORC1 pathway (mTORSer2448, TSC2Ser939, and RPS6Ser235/236). Instead, exercise induced greater phosphorylation of 2 proteins of the mTORC1 pathway (PRAS40Thr246 and p70S6KThr412) in insulin-stimulated muscles, regardless of diet. Insulin resistance induced by a brief HFD was not attributable to greater activation of the mTORC1 or the IKK/NF-κB pathway in muscle, and exercise-induced improvement in insulin sensitivity was not attributable to attenuated activation of these pathways in muscle.

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Section: Discussionmentioning

confidence: 99%

Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

Castorena

Arias

Sharma

et al. 2015

Appl. Physiol. Nutr. Metab.

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“…Moreover, in rats fed a high-fat diet, chronic supplementation with leucine increases insulin sensitivity through enhanced insulin-stimulated protein kinase B (PKB) and mTOR phosphorylation in insulin-target tissues (liver, skeletal muscle, and adipose tissue) [84]. Furthermore, a rapid reduction of feed intake in pigs is observed when fed excess leucine [87], suggesting the need to balance the three branched-chain amino acids in diets.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Nutritional epigenetics with a focus on amino acids: implications for the development and treatment of metabolic syndrome

Dai

et al. 2016

The Journal of Nutritional Biochemistry

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“…As leucine is a natural activator of the mTOR signaling pathway, it is plausible to hypothesize that leucine supplementation recruits mTOR signaling in the hypothalamus, which in turn causes a reduction in food intake. However, the vast majority of the studies that assessed the consequences of leucine supplementation did not find any reduction in food intake, even those studies that observed decreases in body fat mass [19-21,24-27,31-37]. On the other hand, when leucine is directly administered in the CNS through an intracerebroventricular (i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

Oral Leucine Supplementation Is Sensed by the Brain but neither Reduces Food Intake nor Induces an Anorectic Pattern of Gene Expression in the Hypothalamus

et al. 2013

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Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity.

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Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high‐fat diet likely by promoting insulin signaling in insulin‐target tissues

Abstract: Chronic leucine supplementation can increase insulin sensitivity and body weight likely by reducing oxidative stress and improving insulin signaling pathway in rats on HFD.

Cited by 53 publications

References 59 publications

Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

Nutritional epigenetics with a focus on amino acids: implications for the development and treatment of metabolic syndrome

Oral Leucine Supplementation Is Sensed by the Brain but neither Reduces Food Intake nor Induces an Anorectic Pattern of Gene Expression in the Hypothalamus

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