Branched-chain amino acids alter neurobehavioral function in rats

Abstract

Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab 304: E405-E413, 2013. First published December 18, 2012 doi:10.1152/ajpendo.00373.2012.-Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high-sucrose or a high-fat diet with BCAA induces anxiety-like behavior in rats compared with control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high-energy diets with BCAA causes neurobehavioral impairment. Since BCAA are elevated spontaneously in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.branched-chain amino acids; tryptophan; mood disorders; obesity IN THE PAST FEW DECADES, changes in food consumption and sedentary living conditions have contributed to a worldwide obesity epidemic, including in the US, where more than 34% of adults are obese (44,45). Given the high prevalence of obesity and mood disorders, there is an increasing interest in the relationship of these two conditions (2,17,25,33,42,58,62) and in the concept that overnutrition may have a direct causal link to impairment of mental function.Recent studies have revealed that a cluster of metabolites comprised of the branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile), and valine (Val) and their metabolites, as well as the aromatic amino acids (AAA) tyrosine (Tyr) and phenylalanine (Phe), are strongly associated with obesity and insulin resistance in humans (1,10,29,43,67,78). Moreover, a very similar metabolite cluster predicts incident type 2 diabetes in longitudinal studies in humans (64) and, when measured at baseline in obese subjects, also predicts improvement in insulin sensitivity in response to a dietary/behavioral weight loss intervention (63). These findings suggest the possibility that elevated BCAA could be linked to behavioral disorders.BCAA are transported from the blood into the central nervous system (CNS) through the blood-brain barrier (BBB) by the large neutral amino acid transporter 1 (LAT1) (47). LAT1 transports ...

Tryptophan and Kynurenic Acid May Produce an Amplified Effect in Central Fatigue Induced by Chronic Sleep Disorder

“…Thus, this suggests that TRP and KYNA may produce an amplified effect in central fatigue. The role of KYNA in fatigue that we report is supported by the recent findings39 that administration of a branched-chain amino acid that lowers exercise-induced fatigue also reduces the higher levels of KYNA in the brain. Moreover, it has been reported that exogenous KYNA increases fatigability and the administration of KYNA into the hippocampus decreases neurocognition 12.…”

Perinatal western‐type diet and associated gestational weight gain alter postpartum maternal mood

“…During this period, HFD and BCAA groups consumed more kilocalories than the control group [significant main effects of HFD, F (1,68)  = 22.75, p  <   .001; and BCAA, F (1,68)  = 15.63, p  <   .001; Figure 2b], likely due to the greater palatability and/or energy density of these diets (Coppola et al., 2013). However, HFD/BCAA animals gained significantly more weight per kilocalorie consumed than did all other diet groups over the 6 weeks on diet [significant HFD X BCAA interaction, F (1,185)  = 16.84, p  <   .001; post hoc, p  <   .05; Figure 2c], suggesting an effect of diet on metabolic regulation, or digestion efficiency/absorption.…”

“…no. D06050807; n  =   60] (Coppola et al., 2013). The HFD and HFD/BCAA diets provided 4.7 kcal/g; the LFD provided 3.84 kcal/g; and the LFD/BCAA provided 3.85 kcal/g.…”

Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

“…In this study, Kaddurah-Daouk and co-workers identified that lower plasma levels of branched chain amino acids (BCAAs) correlate with positive treatment outcomes. These results on BCAAs in CNS disorders are very timely as Newgard and co-workers determined that supplementation in BCAA was associated with anxiety-like phenotypes in the mouse (Coppola et al 2013 were associated with a particular form of heritable autism with epilepsy (Novarino et al 2012). These three studies suggest that BCAAs (and potentially other metabolites) play a prominent role in CNS disorders and that metabolic profiles can predict treatment outcomes in the clinical setting.…”