BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons.

BACKGROUND: High-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs. METHODS: Three-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted. RESULTS: Using a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic-euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice. CONCLUSION: These findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.

Correlation between newborn weight and serum BCAAs in pregnant women with diabetes.

BACKGROUND: Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for mammals. Maternal BCAAs during pregnancy have been associated with newborn development. Meanwhile, BCAAs have been tightly linked with insulin resistance and diabetes in recent years. Diabetes in pregnancy is a common metabolic disorder. The current study aims to assess the circulating BCAA levels in pregnant women with diabetes and their relationship with neonatal development. METHODS: The serum concentrations of BCAAs and their corresponding branched-chain α-keto acids (BCKAs) catabolites in 33 pregnant women with normal glucose tolerance, 16 pregnant women with type 2 diabetes before pregnancy (PDGM), and 15 pregnant women with gestational diabetes mellitus (GDM) were determined using a liquid chromatography system coupled to a mass spectrometer. The data were tested for normal distribution and homogeneity of variance before statistical analysis. Correlations were computed with the Pearson correlation coefficient. RESULTS: The maternal serum BCAAs and BCKAs levels during late pregnancy were higher in women with PGDM than those in healthy women. Meanwhile, the circulating BCAAs and BCKAs showed no significant changes in women with GDM compared with those in healthy pregnant women. Furthermore, the circulating BCAA and BCKA levels in women with PGDM were positively correlated with the weight of the newborn. The circulating leucine level in women with GDM was positively correlated with the weight of the newborn. BCAA and BCKA levels in healthy pregnant women showed no correlation with newborn weight. CONCLUSIONS: The serum BCAAs in pregnant women with diabetes, which was elevated in PGDM but not GDM, were positively correlated with newborn weight. These findings highlight potential approaches for early identification of high-risk individuals and interventions to reduce the risk of adverse pregnancy outcomes.

Metabolomic analysis of rumen-protected branched-chain amino acids in primiparous dairy cows.

Introduction: Peripartal cows are susceptible to a negative energy balance due to inadequate nutrient intake and high energy requirements for lactation. Improving the energy metabolism of perinatal dairy cows is crucial in increasing production in dairy cows. Methods: In this study, we investigated the impact of rumen-protected branched-chain amino acid (RPBCAA) on the production performance, energy and lipid metabolism, oxidative stress, and immune function of primiparous dairy cows using metabolomics through a single-factor experiment. Twenty healthy primiparous Holstein cows were selected based on body condition scores and expected calving date, and were randomly divided into RPBCAA (n = 10) and control (n = 10) groups. The control group received a basal diet from calving until 21 d in milk, and the RPBCAA group received the basal diet and 44.6 g/d RPLeu, 25.14 g/d RPIle, and 25.43 g/d RPVal. Results: In comparison to the control group, the supplementation of RPBCAA had no significant effect on milk yield and milk composition of the dairy cows. Supplementation with RPBCAA significantly increased the concentrations of insulin, insulin growth factor 1, glucagon, and growth hormones, which are indicators of energy metabolism in postpartum cows. The very low density lipoprotein, fatty acid synthase, acetyl coenzyme A carboxylase, and hormone-sensitive lipase contents of the RPBCAA group were significantly greater than that of the control group; these metrics are related to lipid metabolism. In addition, RPBCAA supplementation significantly increased serum glutathione peroxidase and immunoglobulin G concentrations and decreased malondialdehyde concentrations. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed 414 serum and 430 milk metabolic features. Supplementation with RPBCAA primarily increased concentrations of amino acid and lipid metabolism pathways and upregulated the abundance of serotonin, glutamine, and phosphatidylcholines. Discussion: In summary, adding RPBCAA to the daily ration can influence endocrine function and improve energy metabolism, regulate amino acid and lipid metabolism, mitigate oxidative stress and maintain immune function on primiparous cows in early lactation.

Branching out beyond canonical brown adipocyte function.

Brown adipose tissue has long been functionally characterized as an organ that regulates thermogenesis, body weight set point, and glucose homeostasis. In the May 9, 2024, issue of Cell, Verkerke et al. discover a novel function for brown adipose tissue in processing branched-chain amino acids into antioxidant metabolites that enter the circulation and regulate insulin signaling in the liver.

Home exercise, branched-chain amino acids, and probiotics improve frailty in cirrhosis: A randomized clinical trial.

BACKGROUND: Frailty is a predictive factor of hospitalization, falls, and mortality in patients with cirrhosis, regardless of the degree of liver failure. The aim was to analyze whether a multifactorial intervention consisting of home-based exercise, branched-chain amino acids, and a multistrain probiotic can improve frailty in these patients. METHODS: Outpatients with cirrhosis were classified according to the Liver Frailty Index (LFI). Prefrail and frail patients were randomized into 2 groups. The intervention group was assigned to a multifactorial intervention consisting of exercise at home, branched-chain amino acid supplements, and a multistrain probiotic for 12 months. The control group received standard care. All patients were prospectively followed up every 3 months for 1 year to determine LFI, incidence of falls, emergency room visits, hospitalizations, and mortality. RESULTS: Thirty-two patients were included: 17 patients were assigned to the intervention group and 15 to the control group. In the intervention group, the baseline LFI decreased at 3, 6, 9, and 12 months (p = 0.019 for overall change with respect to the control group). The change in LFI (ΔLFI) at 12 months was -0.71 ± 0.24 in the intervention group and -0.09 ± 0.32 in the control group (p<0.001). During follow-up, patients in the intervention group had a lower 1-year probability of falls (6% vs. 47%, p = 0.03) and emergency room visits (10% vs. 44%, p = 0.04) than patients in the control group. CONCLUSIONS: A long-term multifactorial intervention that included exercise at home, branched-chain amino acids, and a multistrain probiotic improved frailty in outpatients with cirrhosis and was associated with a decrease in the incidence of clinical events such as falls and emergency room visits.

Effect of branched-chain amino acid supplementation and exercise on quadriceps muscle quantity and quality in patients with cirrhosis as assessed by ultrasonography: A randomized controlled trial.

BACKGROUND/AIM: Sarcopenia and myosteatosis are common in patients with cirrhosis. The study aimed to evaluate efficacy of ultrasound to monitor muscle status during branched-chain amino acid (BCAA) supplementation and/or muscle exercise interventional approaches. PATIENTS AND METHODS: A randomized controlled study, included 220 liver cirrhosis patients with Child- Pugh B and C, randomized into a control group (55 patients) received only the standard care, and interventional groups (165 patients) equally distributed into three subgroups, in addition to standard care, they received BCAA, programmed exercise, or BCAA and programmed exercise. At baseline and after 28 days, all participants were subjected to ultrasound-measured quadriceps muscle thickness and echo-intensity, muscle strength using handgrip, performance using short physical performance battery (SPPB), Model for End-Stage Liver Disease (MELD) score and nutritional assessment using 7- point Subjective Global Assessment Score (SGA) and laboratory assessment. RESULTS: All interventional groups showed a significant improvement in the ultrasound detected quadriceps muscle thickness (p = 0.001) and echo intensity, in addition to muscle strength, muscle performance, and SGA. Hematological parameters (hemoglobin and platelet count), biochemical parameters (ALT, AST, bilirubin, creatinine, urea and INR) and MELD score were also improved in the interventional groups. In Child-Pugh B patients BCAA combined with exercise showed an add-on effect. CONCLUSION: BCAA supplements, programed muscle exercise and both are useful interventional methods in improving muscle quality and quantity in cirrhosis patients, which can be monitored by ultrasound. The best results can be achieved by combined intervention in Child-Pugh B, while in Child-Pugh C single intervention may lead to an acceptable improvement. The trial was registered retrospectively in the Clinical Trials Registry (registration number NCT06088550).

Deciphering the Impact of Defecation Frequency on Gut Microbiome Composition and Diversity.

This study explores the impact of defecation frequency on the gut microbiome structure by analyzing fecal samples from individuals categorized by defecation frequency: infrequent (1-3 times/week, n = 4), mid-frequent (4-6 times/week, n = 7), and frequent (daily, n = 9). Utilizing 16S rRNA gene-based sequencing and LC-MS/MS metabolome profiling, significant differences in microbial diversity and community structures among the groups were observed. The infrequent group showed higher microbial diversity, with community structures significantly varying with defecation frequency, a pattern consistent across all sampling time points. The Ruminococcus genus was predominant in the infrequent group, but decreased with more frequent defecation, while the Bacteroides genus was more common in the frequent group, decreasing as defecation frequency lessened. The infrequent group demonstrated enriched biosynthesis genes for aromatic amino acids and branched-chain amino acids (BCAAs), in contrast to the frequent group, which had a higher prevalence of genes for BCAA catabolism. Metabolome analysis revealed higher levels of metabolites derived from aromatic amino acids and BCAA metabolism in the infrequent group, and lower levels of BCAA-derived metabolites in the frequent group, consistent with their predicted metagenomic functions. These findings underscore the importance of considering stool consistency/frequency in understanding the factors influencing the gut microbiome.

Transcriptomics and UHPLC-QQQ-MS analyses reveal the dysregulation of branched chain amino acids metabolism in renal fibrotic rats.

The dysregulated levels of branched chain amino acids (BCAA) contribute to renal fibrosis in chronic kidney disease (CKD), yet specific analysis of BCAA contents and how they are regulated still remain unclear. It is therefore of great scientific interest to understand BCAA catabolism in CKD and develop a sensitive method for simultaneous determination of individual BCAA and their metabolites branched chain α-ketoacids (BCKA). In this work, the important role of BCAA metabolism that drives renal fibrosis in the process of CKD was first revealed by using transcriptomics. The key target genes controlling BCAA metabolism were then validated, that is, mRNA levels of BCKDHA and BCKDHB, the regulating rate-limiting enzymes during BCAA metabolism were abnormally reduced by quantitative PCR (qPCR), and a similar drop-off trend of protein expression of BCKDH, HIBCH and MCCC2 that are closely related to BCAA metabolism was also confirmed by western blotting. Furthermore, we established a novel strategy that simultaneously determines 6 individual BCAA and BCKA in serum and tissue. The method based on dansylhydrazine derivatization and ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QQQ-MS) achieved to simultaneously determine the contents of BCAA and BCKA, which is efficient and stable. Compared with normal rats, levels of BCAA including leucine, isoleucine and valine in serum and kidney of CKD rats was decreased, while BCKA including α-ketoisocaproic acid, α-ketomethylvaleric acid and α-ketoisovaleric acid was increased. Together, these findings revealed the abnormality of BCAA metabolism in driving the course of kidney fibrosis and CKD. Our current study sheds new light on changes in BCAA metabolism during CKD, and may facilitate development of drugs to treat CKD and renal fibrosis.

Serum branched-chain amino acid levels are associated with fracture risk in Japanese women.

AIM: Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women. METHODS: During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis. RESULTS: The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA. CONCLUSIONS: Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; 24: 603-608.

The ilv2 gene, encoding acetolactate synthase for branched chain amino acid biosynthesis, is required for plant pathogenicity by Leptosphaeria maculans.

BACKGROUND: Control of blackleg disease of canola caused by the fungus Leptosphaeria maculans relies on strategies such as the inhibition of growth with fungicides. However, other chemicals are used during canola cultivation, including fertilizers and herbicides. There is widespread use of herbicides that target the acetolactate synthase (ALS) enzyme involved in branched chain amino acid synthesis and low levels of these amino acids within leaves of Brassica species. In L. maculans the ilv2 gene encodes ALS and thus ALS-inhibiting herbicides may inadvertently impact the fungus. METHODS AND RESULTS: Here, the impact of a commercial herbicide targeting ALS and mutation of the homologous ilv2 gene in L. maculans was explored. Exposure to herbicide had limited impact on growth in vitro but reduced lesion sizes in plant disease experiments. Furthermore, the mutation of the ilv2 gene via CRISPR-Cas9 gene editing rendered the fungus non-pathogenic. CONCLUSION: Herbicide applications can influence disease outcome, but likely to a minor extent.

Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress.

Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.

Molecular and physiological characterization of AIP1, encoding the acetolactate synthase regulatory subunit in rice.

Flooding deprives plants of oxygen and thereby causes severe stress by interfering with energy production, leading to growth retardation. Enzymes and metabolites may help protect plants from waterlogging and hypoxic environmental conditions. Acetolactate synthase (ALS) is a key enzyme in the biosynthesis of branched-chain amino acids (BCAAs), providing the building blocks for proteins and various secondary metabolites. Additionally, under energy-poor conditions, free BCAAs can be used as an alternative energy source by mitochondria through a catabolic enzyme chain reaction. In this study, we characterized ALS-INTERACTING PROTEIN 1 (OsAIP1), which encodes the regulatory subunit of ALS in rice (Oryza sativa). This gene was expressed in all parts of the rice plant, and its expression level was significantly higher in submerged and low-oxygen environments. Rice transformants overexpressing OsAIP1 showed a higher survival rate under hypoxic stress than did non-transgenic control plants under the same conditions. The OsAIP1-overexpressing plants accumulated increased levels of BCAAs, demonstrating that OsAIP1 is an important factor in the hypoxia resistance mechanism. These results suggest that ALS proteins are part of a defense mechanism that improves the tolerance of plants to low-oxygen environments.

Efficacy of amino acids in sports nutrition- review of clinical evidences.

The efficacy of amino acids as popular sports supplements has triggered debates, with their impact on athletic performance varying across sports disciplines due to diversity and heterogeneity in clinical trials. This review evaluates the ergogenic potential of amino acids, by critical appraisal of results of clinical trials of Branched chain amino acids (BCAAs), arginine, glutamine, citrulline, ß-alanine, and taurine, performed on elite sportsmen from various land and water sports. Clinical trials reviewed here confirm notable physiological benefits thereby supporting the claim that BCAA, citrulline and arginine in various doses can have positive effects on endurance and overall performance in sportsperson. Furthermore, results of clinical trials and metabolomic studies indicate that in future it would be more beneficial to design precise formulations to target the requirement of specific sports. For instance, some combinations of amino acids may be more suitable for long term endurance and some others may be suitable for short burst of excessive energy. The most important insights from this review are the identification of three key areas where research is urgently needed: a) Biomarkers that can identify the physiological end points and to distinguish the specific role of amino acid as anti-fatigue or reducing muscle soreness or enhancing energy b) In-depth sports-wise clinical trials on elite sportsperson to understand the ergogenic needs for the particular sports c) Design of precision formula for similar types of sports instead of common supplements.

Stereoselective amino acid synthesis by photobiocatalytic oxidative coupling.

Photobiocatalysis-where light is used to expand the reactivity of an enzyme-has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts1. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes2-9. Here we report photobiocatalytic asymmetric sp3-sp3 oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. We repurpose a family of pyridoxal-5'-phosphate-dependent enzymes, threonine aldolases10-12, for the α-C-H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids 13-15 possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion. Cooperative photoredox-pyridoxal biocatalysis provides a platform for sp3-sp3 oxidative coupling16, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology.

Adding Branched-Chain Amino Acids and Vitamin D to Whey Protein Is More Effective than Protein Alone in Preserving Fat Free Mass and Muscle Strength in the First Month after Sleeve Gastrectomy.

OBJECTIVES: Sleeve gastrectomy (SG) is one of the most commonly performed weight loss (WL) bariatric procedures. The main goal of WL is reducing total body weight (TBW) and fat mass (FM). However, TBW loss is systematically accompanied by a decline in fat-free mass (FFM), predominantly in the first post-surgical month, despite protein supplementation. Branched-chain amino acids (BCAAs) and vitamin D seem to attenuate loss of FFM and, thus, reduce the decline in muscle strength (MS). However, data on the role of an integrated supplementation with whey protein plus BCAAs plus vitamin D (P+BCAAs+Vit.D) vs. protein alone on total weight loss (TWL), fat mass (FM), fat-free mass (FFM), and (MS) in the first month after SG are lacking. Therefore, the present study aims to evaluate the impact of P+BCAAs+Vit.D vs. protein alone supplementation on TWL, FM, FFM, and MS in the first month after SG. MATERIALS AND METHODS: Before SG and at 1 month afterward, we prospectively measured and compared TBW, FM, FFM, and MS in 57 patients who received either a supplementation with P+BCAAs+Vit.D (n = 31) or protein alone (n = 26). The impact of P+BCAAs+Vit.D and protein alone supplementation on clinical status was also evaluated. RESULTS: Despite non-significant variation in TBW, FM decreased more significantly (18.5% vs. 13.2%, p = 0.023) with the P+BCAA+Vit.D supplementation compared to protein alone. Furthermore, the P+BCAA+Vit.D group showed a significantly lower decrease in FFM (4.1% vs. 11.4%, p < 0.001) and MS (3.8% vs. 18.5%, p < 0.001) compared to the protein alone group. No significant alterations in clinical status were seen in either group. CONCLUSION: P+BCAA+Vit.D supplementation is more effective than protein alone in determining FM loss and is associated with a lower decrease in FFM and MS, without interfering with clinical status in patients 1 month after SG.

Sex differences in cachexia and branched-chain amino acid metabolism following chemotherapy in mice.

Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten-week-old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5-fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p < 0.05 for all). Drug treatment increased plasma BCAA only in males, but BCAA concentrations in the skeletal muscle of both sexes were decreased; this decrease was more profound in males (p = 0.0097). In addition, muscle expression of the BCAA transporter LAT1 was reduced; this reduction was more severe in females (p = 0.0264). In both sexes, the (inhibitory) phosphorylation of BCKD-E1αser293 was increased along with decreased BCKD activity. In the liver, drug treatment increased BCAA concentrations and LAT1 expression, but BCKD activity was suppressed in both sexes (p < 0.05 for all). Our results demonstrate that altered BCAA metabolism may contribute to chemotherapy-induced cachexia in a sex-dependent manner.

Branched-chain amino acid supplementation drives dynamic changes in gut microbiota without impairing glucose and lipid homeostasis at the different stages of insulin resistance in mice on a high-fat diet.

OBJECTIVE: The potential role of dietary branched-chain amino acids on circulating branched-chain amino acid levels and their relationship with metabolic health are complex, and the literature is inconsistent. We aimed to explore the dynamic effects of branched-chain amino acid supplementation on glucose and lipid homeostasis at different stages of insulin resistance in high-fat diet-fed mice. METHODS: Male C57BL/6J mice were fed with a normal chow diet, high-fat diet, or high-fat diet supplemented with 100% branched-chain amino acids for 12 or 24 wk. Metabolic parameters and gut microbiota profiling were performed at these two time points. RESULTS: High-fat diet feeding caused varying degrees of branched-chain amino acid metabolic disorders in two different stages of insulin resistance. Supplementing with branched-chain amino acids further exacerbated branched-chain amino acid accumulation in the early stage of insulin resistance (12 wk), while adding branched-chain amino acids did not further elevate branched-chain amino acid levels in the hyperglycemia and hyperinsulinemia stage (24 wk). Compared with the high-fat diet group, branched-chain amino acid supplementation did not affect body weight; liver total cholesterol and triacylglycerol levels; and serum glucose, insulin, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels as well as glucose tolerance at these two time points but triggered dynamic changes in the gut bacterial diversity and gut microbiota composition and abundance, especially in the genus associated with obesity and related metabolic disorders. CONCLUSION: Dietary branched-chain amino acid supplementation drives dynamic changes in circulating branched-chain amino acid levels and gut microbiome without subsequent effects on glucose and lipid homeostasis in high-fat diet-induced obese mice within the parameters of our study.

Bcat2-Mediated Branched-Chain Amino Acid Catabolism Is Linked to the Aggravated Inflammation in Obese with Psoriasis Mice.

SCOPE: The global prevalence of obesity has significantly increased, presenting a major health challenge. High-fat diet (HFD)-induced obesity is closely related to the disease severity of psoriasis, but the mechanism is not fully understood. METHODS AND RESULTS: The study utilizes the HFD-induced obesity model along with an imiquimod (IMQ)-induced psoriasis-like mouse model (HFD-IMQ) to conduct transcriptomics and metabolomic analyses. HFD-induced obese mice exhibits more severe psoriasis-like lesions compared to normal diet (ND)-IMQ mice. The expression of genes of the IL-17 signaling pathway (IL-17A, IL-17F, S100A9, CCL20, CXCL1) is significantly upregulated, leading to an accumulation of T cells and neutrophils in the skin. Moreover, the study finds that there is an inhibition of the branched-chain amino acids (BCAAs) catabolism pathway, and the key gene branched-chain amino transferase 2 (Bcat2) is significantly downregulated, and the levels of leucine, isoleucine, and valine are elevated in the HFD-IMQ mice. Furthermore, the study finds that the peroxisome proliferator-activated receptor gamma (PPAR γ) is inhibited, while STAT3 activity is promoted in HFD-IMQ mice. CONCLUSION: HFD-induced obesity significantly amplifies IL-17 signaling and exacerbates psoriasis, with a potential role played by Bcat2-mediated BCAAs metabolism. The study suggests that BCAA catabolism and PPAR γ-STAT3 exacerbate inflammation in psoriasis with obesity.

Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology.

The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health.

Study on anti-BmNPV mechanism of branched-chain amino acid aminotransferases in silkworm.

Bombyx mori nucleopolyhedrovirus (BmNPV) is the most important virus that threatens sericulture industry. At present, there is no effective treatment for BmNPV infection in silkworms, and lncRNA plays an important role in biological immune response and host-virus interaction, but there are relatively few studies in silkworms. In this study, the four midgut tissue samples of the resistance strain NB (NB) and susceptible strain 306 (306) and the NB and 306 continuously infected with BmNPV for 96 h are used for whole transcriptome sequencing to analyze the differences in the genetic background of NB and 306 and the differences after inoculation of BmNPV, and the significantly different mRNA, miRNA and lnRNA between NB and 306 after BmNPV inoculation were screened. By comparing NB and 306, 2651 significantly different mRNAs, 57 significantly different miRNAs and 198 significantly different lncRNAs were screened. By comparing NB and 306 after BmNPV inoculation, 2684 significantly different mRNAs, 39 significantly different miRNAs and 125 significantly different lncRNAs were screened. According to the significantly different mRNA, miRNA and lncRNA screened from NB and 306 and NB and 306 after virus inoculation, the mRNA-miRNA-lncRNA regulatory network was constructed before and after virus inoculation, and the BmBCAT-Bomo_chr7_8305-MSTRG.3236.2 regulatory axis was screened from them, and it was found that BmBCAT was not Bomo_chr7_8305 regulated in the genetic background, after viral infection, MSTRG.3236.2 competes for binding Bomo_chr7_8305 regulates BmBCAT. The whole transcriptome sequencing results were verified by qPCR and the time-series expression analysis was performed to prove the reliability of the regulatory network. The BmBCAT-Bomo_chr7_8305-MSTRG.3236.2 regulatory axis may play a potential role in the interaction between silkworms and BmNPV. These results provide new insights into the interaction mechanism between silkworms and BmNPV.