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Objectives: Diabetes mellitus is associated with dyslipidemia, which contributes to a higher risk of thrombosis, atherosclerosis and cardiovascular disease. This study evaluated the effects of leucine and resistance training on the serum lipid profile in rats with streptozotocin-induced diabetes for 8 weeks., Methods: Wistar rats with neonatal streptozotocin-induced diabetes were treated with leucine supplementation (5%) and/or resistance training (3 days per week) for 8 weeks, and divided in DL (diabetic and leucine), DT (diabetic and resistance training group) and DLT (diabetic, leucine and resistance training) groups. Others 2 groups of animals received isonitrogen AIN-93M diet that was defined as a control diet: group D (diabetic untreated) and group C (non-diabetic)., Results: The decrease in serum total cholesterol and increase in high-density lipoprotein cholesterol (HDL-C) was observed in the resistance training-induced diabetic rats when compared with diabetic rats. There was no change in serum lipid profile in leucine-supplemented diabetic rats and no synergistic effect of leucine and resistance training. The fasting glucose levels were reduced in all animals treated compared to D group., Conclusion: The diabetic trained rats demonstrate a protective effect of resistance training on the serum lipid profile.

Background: Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation., Aim: The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats., Methods: Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed., Results: Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively., Conclusions: Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

Leucine supplementation and resistance training positively influence the protein translation process and the cell signaling mTOR (mammalian target of rapamycin) pathway that regulates muscle protein balance and muscle remodeling, and thus may be therapeutic to diabetic myopathy. However, the effect of a combined intervention has not been well studied. Forty male Wistar rats were divided into five groups, control (C), diabetic control (D), diabetic + trained (DT), diabetic + L-leucine (DL), diabetic + L-leucine + trained (DLT). The supplementation of 5% leucine in chow, and resistance training were conducted for 8 weeks postweaning of rats. The extensor digitorum longus was used to assess signaling proteins involved in muscle protein synthesis, and the gastrocnemius and soleus were used for determination of muscle weight. Blood samples were collected for biochemical assays. Strength and ambulation tests were employed to evaluate motor performance. Results showed that both leucine supplementation and resistance training elevated the activity of mTOR-p70S6K in diabetic rats ( P  < 0.05). Moreover, though leucine supplementation in combination with resistance training demonstrated synergistic effects on p70S6K ( P  < 0.05), both treatments were capable of recovering motor performance ( P  <  0.05 ). In conclusion, 5% leucine supplementation combined with resistance training has the potential to attenuate muscle loss and motor performance decrements in diabetic rats, at least in part through increased protein synthesis., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Several studies have highlighted the potential of leucine supplementation for the treatment of metabolic diseases including type 2 diabetes and obesity. Caloric restriction is a common approach to improve the health in diabetic and obese subjects. However, very few studies assessed the effects of leucine supplementation in calorie-restricted animals. Rats were subjected to a 30% calorie-restricted diet for 6 weeks to study the effects of leucine supplementation on protein status markers and lipid metabolism. Caloric restriction reduced the body weight. However, increased leucine intake preserved body lean mass and protein mass and improved protein anabolism as indicated by the increased circulating levels of albumin and insulin-like growth factor-1 (IGF-1), and the liver expression of albumin and IGF-1 messenger RNA. Leucine supplementation also increased the circulating levels of interleukin-6 and leptin but did not affect the tumour necrosis factor-α and monocyte chemotactic protein-1 concentrations. Ketone bodies were increased in rats consuming a leucine-rich diet, but we observed no changes in cholesterol or triglycerides concentrations. Caloric restriction reduced the liver expression of peroxisome proliferator activated receptor-α and glucose-6-phosphatase, whereas leucine supplementation increased the liver expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA) reductase and sterol regulatory element-binding transcription factor 1. A leucine-rich diet during caloric restriction preserved whole body protein mass and improved markers of protein anabolism. In addition, leucine modulated the hepatic lipid metabolism. These results indicate that increased leucine intake may be useful in preventing excessive protein waste in conditions of large weight loss., (Copyright © 2013 John Wiley & Sons, Ltd.)

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.

This study evaluated the effect of leucine on the protein status of rats submitted to 50% food restriction for 1 week, followed by 2 weeks of nutritional recovery. A significant increase of serum insulin-like growth factor 1 and protein/RNA ratio in the liver was observed in leucine-supplemented rats. There was no change in carcass, liver, or gastrocnemius protein content when compared with control animals. The supplementation tested did not favor protein status, although it improved some indicators of an anabolic state.

Certain amino acids, such as leucine (Leu) are not only substrates for protein synthesis but also are important regulators of protein metabolism. Moreover, it is known that alterations in intrauterine growth favor the development of chronic diseases in adulthood. Therefore, we investigated the role of Leu in combination with other BCAA on effects that are induced by maternal protein restriction on fetal growth. Wistar rats were divided into 4 groups according to the diet provided during pregnancy: control (C; 20% casein); V+I [5% casein + 2% L-valine (Val) + 2% L-isoleucine (Ile)]; KYT [5% casein + 1.8% L-lysine (Lys) + 1.2% L-tyrosine (Tyr) + 1% L-threonine (Thr)]; and BCAA (5% casein + 1.8% L-Leu + 1.2% L-Val + 1% L-Ile). Maternal protein restriction reduced the growth and organ weight of the offspring of dams receiving the V+I and KYT diets compared with the C group. Supplementation with BCAA reversed this growth deficit, minimizing the difference or restoring the mass of organs and carcass fat, the liver and muscle protein, and the RNA concentrations compared with newborns in the C group (P < 0.05). These effects could be explained by the activation of the mTOR signaling pathway, because phosphorylation of 4E-BP1 in the liver of offspring of the BCAA group was greater than that in the C, V+I, and KYT groups. The present results identify a critical role for Leu in association with other BCAA in the activation of the mTOR signaling pathway for the control of altered intrauterine growth induced by a maternal low-protein diet.

Objective: Aging is characterized by alterations in body composition such as an increase in body fat and decreases in muscle mass (sarcopenia) and bone density (osteopenia). Leucine supplementation has been shown to acutely stimulate protein synthesis and to decrease body fat. However, the long-term effect of consistent leucine supplementation is not well defined. This study investigated the effect of leucine supplementation during aging., Methods: Six-month-old rats were divided into three groups: an adult group (n = 10) euthanized at 6 mo of age, a leucine group (n = 16) that received a diet supplemented with 4% leucine for 40 wk, and a control group (n = 19) that received the control diet for 40 wk. The following parameters were evaluated: body weight, food intake, chemical carcass composition, indicators of acquired chronic diseases, and indicators of protein nutritional status., Results: Body weight and fat were lower in the leucine group after 40 wk of supplementation compared with the control group but still higher than in the adult group. The lipid and glycemic profiles were equally altered in the control and leucine groups because of aging. In addition, leucine supplementation did not affect the changes in protein status parameters associated with aging, such as decreases in body and muscle protein and total serum protein., Conclusion: The results indicate that leucine supplementation attenuates body fat gain during aging but does not affect risk indicators of acquired chronic diseases. Furthermore, supplemented animals did not show signs of a prevention of the decrease in lean mass associated with aging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

An important role in protein-energy metabolism has been attributed to leucine because of its long-term effects on body fat reduction and on the improvement of some indicators of protein status in rodents. The present study investigated the influence of leucine supplementation on the body composition and protein status of rats during the early phase of weight loss, which is characterized by a rapid loss of body weight. Thirty adult male Wistar rats were divided into 2 groups, a control and a leucine group (diet supplemented with 0.59% L-leucine), and were submitted to 1 week of 50% food restriction. The following parameters were evaluated: chemical carcass composition, protein and RNA content in liver and gastrocnemius muscle, and serum concentrations of insulin-like growth factor-1 and corticosterone. A higher liver weight and liver protein content were observed in the supplemented group (p < 0.05). However, no difference in body fat was found between groups (p > 0.05). The results indicate that low-dose leucine supplementation favors liver protein status but does not reduce body fat in rats during the early phase of rapid weight loss.

Although many studies have shown that amino acid ingestion acutely stimulates protein anabolism, only few studies have investigated whether long-term supplementation promotes changes in body composition. We therefore tested the hypothesis that l-leucine (LEU) and l-phenylalanine (PHE) supplementation might have a positive impact on the body composition of rats submitted to intermittent periods of food restriction and refeeding (weight cycling or WC). The WC protocol comprised three cycles, each consisting of 1 week of 50% food restriction followed by 2 weeks of ad libitum ingestion. The groups submitted to WC ingested the control diet (WC-CON) or the diet supplemented with LEU+PHE (WC-AA). A pair-fed group receiving the control diet (PF-CON) was used as a reference for the effects of WC. Although food intake was the same in all groups, higher body weight and energy efficiency were observed in the WC-AA group compared to the PF-CON and WC-CON groups although not significantly in relation to the latter. These results were the consequence of a significant increase of lean body mass and body protein content in the WC-AA group compared to the PF-CON and WC-CON groups. The WC-CON and WC-AA groups presented 36.1% and 18.9% more body fat, respectively, than the PF-CON group but this difference was not significant. Neither fasting insulin nor glucose concentration nor postprandial insulin secretion was significantly affected by the supplemented diet. In conclusion, supplementation with LEU+PHE improved the body composition profile of rats submitted to WC, mainly by increasing lean body mass and body protein content.

Objective: Acute administration of leucine has been shown to stimulate certain protein synthesis related anabolic processes. However, the effect of chronic leucine administration in a catabolic situation caused by food restriction (FR) has not been established. We therefore evaluated the effect of chronic leucine supplementation on the body composition and some indicators of protein nutritional status of rats submitted to FR., Methods: Adult male Wistar rats were submitted to 50% FR for 6 weeks. The control group received the AIN-93M diet and the leucine group received the same diet supplemented with 5.91 g L-leucine/kg ration. We then determined carcass chemical composition, serum leptin, albumin and total protein concentrations, and protein, DNA and RNA concentrations in gastrocnemius muscle and liver., Results: No difference in final body weight was observed between groups. However, the leucine group presented a lower amount of body fat (P < 0.05). Leptin concentration showed a directly proportional correlation with the amount of body fat (r = 0.88, P < 0.05), but no significant difference in serum leptin concentration was observed between groups (P = 0.08). Regarding protein nutritional status, liver protein concentration was higher in the leucine group (P < 0.05). In the gastrocnemius muscle, a higher RNA concentration (P < 0.05) and a tendency towards higher DNA concentration (P = 0.06) were observed in the leucine group., Conclusion: The results indicate that low-dose leucine supplementation increases body fat loss and improves liver protein status and the capacity of muscle protein synthesis in rats submitted to FR.

Abstract Background Studies suggest that leucine supplementation (LS) has a therapeutic potential to prevent obesity and to promote glucose homeostasis. Furthermore, regular physical exercise is a widely accepted strategy for body weight maintenance and also for the prevention of obesity. The aim of this study was to determine the effect of chronic LS alone or combined with endurance training (ET) as potential approaches for reversing the insulin resistance and obesity induced by a high-fat diet (HFD) in rats. Methods Forty-seven rats were randomly divided into two groups. Animals were fed a control diet-low fat (n = 10) or HFD (n = 37). After 15 weeks on HFD, all rats received the control diet-low fat and were randomly divided according to treatment: reference (REF), LS, ET, and LS+ET (n = 7-8 rats per group). After 6 weeks of treatment, the animals were sacrificed and body composition, fat cell volume, and serum concentrations of total cholesterol, HDL-cholesterol, triacylglycerol, glucose, adiponectin, leptin and tumor necrosis factor-alpha (TNF-α) were analyzed. Results At the end of the sixth week of treatment, there was no significant difference in body weight between the REF, LS, ET and LS+ET groups. However, ET increased lean body mass in rats (P = 0.019). In addition, ET was more effective than LS in reducing adiposity (P = 0.019), serum insulin (P = 0.022) and TNF-α (P = 0.044). Conversely, LS increased serum adiponectin (P = 0.021) levels and reduced serum total cholesterol concentration (P = 0.042). Conclusions The results showed that LS had no beneficial effects on insulin sensitivity or adiposity in previously obese rats. On the other hand, LS was effective in increasing adiponectin levels and in reducing total cholesterol concentration.

Although branched-chain amino acids (BCAA) are commonly used as a strategy to recover nutritional status of critically ill patients, recent findings on their role as immunonutrients have been associated with unfavorable outcomes, especially in obese patients. The present study aimed to explore the effects of different BCAA supplementation protocols in the inflammatory response of LPS-stimulated RAW 264.7 macrophages. Cell cultures were divided into five groups, with and without BCAA supplementation, (2 mmol/L of each amino acid). Then, cell cultures followed three different treatment protocols, consisting of a pretreatment (PT), an acute treatment (AT), and a chronic treatment (CT) with BCAA and LPS stimulation (1 µg/mL). Cell viability was analyzed by MTT assay, NO production was assessed by the Griess reaction and IL-6, IL-10, TNF-α and PGE2 synthesis, was evaluated by ELISA. BCAA significantly increased cell viability in AT and CT protocols, and NO and IL-10 synthesis in all treatment protocols. IL-6 synthesis was only increased in PT and CT protocols. TNF-α and PGE2 synthesis were not altered in any of the protocols and groups. BCAA supplementation was able to increase both pro and anti-inflammatory mediators synthesis by RAW 264.7 macrophages, which was influenced by the protocol applied. Moreover, these parameters were significantly increased by isoleucine supplementation, highlighting a potential research field for future studies. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs) have been associated with immunomodulation since the mid-1970s and 1980s and have been used in the nutritional therapy of critically ill patients. Evidence shows that BCAAs can directly contribute to immune cell function, aiding recovery of an impaired immune system, as well as improving the nutritional status in cancer and liver diseases. Branched-chain amino acids may also play a role in treatment of patients with sepsis or trauma, contributing to improved clinical outcomes and survival. Branched-chain amino acids, especially leucine, are activators of the mammalian target of rapamycin (mTOR), which, in turn, interacts with several signaling pathways involved in biological mechanisms of insulin action, protein synthesis, mitochondrial biogenesis, inflammation, and lipid metabolism. Although many in vitro and human and animal model studies have provided evidence for the biological activity of BCAAs, findings have been conflicting, and the mechanisms of action of these amino acids are still poorly understood. This review addresses several aspects related to BCAAs, including their transport, oxidation, and mechanisms of action, as well as their role in nutritional therapy and immunomodulation. [ABSTRACT FROM AUTHOR]

Certain amino acids, such as leucine (Leu) are not only substrates for protein synthesis but also are important regulators of protein metabolism. Moreover, it is known that alterations in intrauterine growth favor the development of chronic diseases in adulthood. Therefore, we investigated the role of Leu in combination with other BCAA on effects that are induced by maternal protein restriction on fetal growth. Wistar rats were divided into 4 groups according to the diet provided during pregnancy: control (C; 20% casein); V+I [5% casein + 2% l-valine (Val) + 2% l-isoleucine (Ile)]; KYT [5% casein + 1.8% l-lysine (Lys) + 1.2% l-tyrosine (Tyr) + 1% l-threonine (Thr)]; and BCAA (5% casein + 1.8% l-Leu + 1.2% l-Val + 1% l-Ile). Maternal protein restriction reduced the growth and organ weight of the offspring of dams receiving the V+I and KYT diets compared with the C group. Supplementation with BCAA reversed this growth deficit, minimizing the difference or restoring the mass of organs and carcass fat, the liver and muscle protein, and the RNA concentrations compared with newborns in the C group (P < 0.05). These effects could be explained by the activation of the mTOR signaling pathway, because phosphorylation of 4E-BP1 in the liver of offspring of the BCAA group was greater than that in the C, V+I, and KYT groups. The present results identify a critical role for Leu in association with other BCAA in the activation of the mTOR signaling pathway for the control of altered intrauterine growth induced by a maternal low-protein diet. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate whether Branchedchain amino acids (BCAAs) supplementation had any beneficial effects on growth and metabolic parameters of young rats submitted to chronic aerobic exercise. Thirty-two young rats (age: 21-d) were randomly assigned to four experimental groups (n = 8): Supplemented Trained (Sup/Ex), Control Trained (Ctrl/Ex), Supplemented Sedentary (Sup/Sed) and Control Sedentary (Ctrl/Sed). The trained groups underwent a five-week swimming protocol and received supplemented (45 mg BCAA/body weight/day) or control ration. Trained animals presented a lower body length and a higher cartilage weight, regardless of supplementation. Physical activity was responsible for a substantial reduction in proteoglycan synthesis in cartilage tissue, and BCAA supplementation was able to attenuate this reduction and also to improve glycogen stores in the liver, although no major differences were found in body growth associated to this supplementation. [ABSTRACT FROM AUTHOR]