Leucine supplementation at the onset of high-fat feeding does not prevent weight gain or improve glycemic regulation in male Sprague-Dawley rats

Abstract

Obesity is a major public health concern and it is essential to identify effective treatments and preventative strategies to stop continued increases in obesity rates. The potential functional roles of the branched chain amino acid leucine make this amino acid an attractive candidate for the treatment and/or prevention of obesity. The objective of this study was to determine if long-term leucine supplementation could prevent the development of obesity and reduce the risk factors for chronic disease in rats fed a high-fat (60 % fat) diet. Male Sprague-Dawley rats (n = 30 per dietary treatment) were meal-fed (3 meals/day) either a control, low-fat diet (LF), control + leucine (LFL), high-fat (HF), or high-fat + leucine (HFL) for 42 days. On day 42, rats were sacrificed at 0, 30, or 90 min postprandial. Animals fed the HF and HFL diets had higher (P < 0.05) final body weights and weight gain compared to animals fed the LF and LFL diets. Leucine supplementation increased epididymal fat mass (P < 0.05) and decreased muscle mass (P < 0.05). There was no effect of leucine supplementation on postprandial glucose or insulin response. However, there was a significant effect (P < 0.05) of diet and time on free fatty acid concentrations. There was no effect of leucine on muscle markers of protein synthesis (4E-BP1, p70S6K) or energy metabolism (Akt, AMPK). Leucine supplementation decreased (P < 0.05) PGC1α expression and increased (P < 0.05) PPARγ expression in skeletal muscle. In conclusion, long-term leucine supplementation does not prevent weight gain, improve body composition, or improve glycemic control in rats fed a high-fat diet.

Preliminary study: Leucine Supplementation Exacerbates Muscle Wasting Independent of the Ubiquitin-Proteasome System

“…Not only did leucine fail to attenuate cancer cachexia, to our knowledge we are among the first to provide evidence suggesting that chronic, long-term leucine treatment seems to exacerbate the loss of body weight and muscle mass. This is in accordance with a finding by Baum et al (2016) in which rats fed a high-fat diet had lower muscle masses after being fed leucine for 6 weeks, which is longer than any cachexia-related study has been performed to date.…”

“…It has been shown by Liang et al (2014) that leucine increases AMPK activity, which in turn activates PGC1α. In addition, several studies have demonstrated leucine's effect to increase PGC1α mRNA Junior, 2016;Liang 2014;Lee, 2019), however a 6-week study on the effects of leucine on rats fed a high-fat diet found that PGC1α decreased (Baum et al, 2016).…”

“…Peters et al (2011), Salomao et al (2012), and Viana et al (2015) all found a similar result. One of the few studies involving longer supplementation (6 weeks) with leucine showed that leucine decreased muscle mass in rats fed a high-fat diet (Baum et al, 2016). In addition, Lee et al (2019) demonstrated that muscle mass loss was exacerbated in LLC tumor-bearing mice after 28 days of low-dose leucine supplementation.…”

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

“…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].…”

Are BCAAs Mere Biomarkers of Diabetes?

“…While a number of studies demonstrate that either amino acid mixture or BCAA supplementation have beneficial effects on protein turnover and muscle wasting in patients with cirrhosis, kidney failure, cancer, or sepsis, [14][15][16][17][18][19][20][21][22][23][24][25] mounting evidence suggests that amino acids/BCAAs or their metabolized keto acids lead to hyperactivation of mTOR signaling, 7,26-28 induction of oxidative stress, 29-32 mitochondrial dysfunction, 33,34 apoptosis, 35,36 and more importantly, insulin resistance and/or impaired glucose metabolism. 7,[26][27][28][37][38][39][40][41][42][43][44] Consistent with these findings, recent studies demonstrate that a BCAA metabolite elevated in diabetic individuals can drive vascular fatty acid transport in muscle and induce insulin resistance in mice 44 and a defective muscle BCAA metabolism induces impaired lipid metabolism and insulin resistance.45 On the other hand, deprivation of a single or all three BCAAs improves insulin sensitivity and glycemic control in either chow-or High-Fat Diet (HFD)-fed, or genetically diabetic rodents.46-48 These findings strongly indicate not only a correlative, but also a causative role of circulating BCAAs and their oxidized intermediates in the development of insulin resistance and diabetes. As such, it is important to advance our understanding of BCAA regulatory mechanisms that would allow us to explain the reasons for high circulating levels of BCAAs found in obese and diabetic individuals.…”