Restriction Of Branched-chain Amino Acids Research Articles (Page 1)

Caloric restriction is well-established as a robust intervention that may extend lifespan and improve metabolic health across species with effects that are increasingly attributed to both host metabolic remodeling and alterations in the gut microbiota. Recent studies suggest that restricting specific dietary components can replicate these benefits. While methionine and branched-chain amino acid restriction improve metabolism and modulate the gut microbiome, the effects of other nutrients remain unclear. Here, we explore the effects of methionine, tryptophan and niacin deprivation on host intestinal gene expression and gut microbiota using female murine models. Through transcriptomic analysis of the intestinal tissue, we found that transient dietary restriction of methionine, tryptophan, and niacin induced significant changes in intestinal gene expression, particularly in genes involved in oxidative phosphorylation and ATP production. Single-cell analysis revealed that dietary restriction of those nutrients led to an increase in intestinal immune cell populations. Gut microbiota profiling also revealed that transient deprivation of those nutrients resulted in changes in microbial composition, with an increased relative abundance of Lactobacillus species observed in some cases. Our findings highlight the potential of targeted nutrient restriction as a strategy to reprogram host-microbiome interactions.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-18046-2.

Maple Syrup Urine Disease (MSUD) and Type 1 Diabetes Mellitus (T1DM) are two distinct metabolic disorders with unique dietary management requirements. While MSUD necessitates strict restriction of branched-chain amino acids (BCAAs), T1DM requires precise carbohydrate counting to maintain optimal glycemic control. We report two cases of patients diagnosed with both MSUD and T1DM, highlighting the challenges and strategies in dietary management. Case 1, a 5-year-old girl, was diagnosed with T1DM after presenting with hyperglycemia and metabolic acidosis, despite previously stable MSUD management. The dietary regimen was modified to include a leucine-free amino acid formula and controlled carbohydrate intake to stabilize both leucine and glucose levels. Case 2, an 11-year-old boy with the diagnosis of MSUD, presented with hyperglycemia during a routine follow-up. Dietary management involved increasing the leucine-free formula while reducing carbohydrate intake to maintain metabolic control. Both cases emphasize the importance of individualized dietary plans, integrating BCAA restriction and carbohydrate regulation to prevent metabolic crises and achieve optimal glycemic control. These cases also underscore the need for a multidisciplinary approach involving pediatric endocrinologists, metabolic specialists, and dietitians to navigate the complexities of dual metabolic disorders effectively. Further studies are warranted to explore long-term outcomes and potential therapeutic targets in patients with concurrent MSUD and T1DM.

To explore the effects of branched-chain amino acids (BCAAs) on nonalcoholic fatty pancreas disease (NAFPD) and its possible mechanism in high-fat diet (HFD) induced mice. Pancreatic morphology and lipid infiltration was assessed by hematoxylin-eosin staining and immunohistochemistry, and lipid levels in the pancreas were determined using colorimetric enzymatic method. Relevant mechanism was investigated using western blotting and biochemical test. In HFD-fed mice, dietary BCAAs restriction could attenuate body weight increase, improve glucose metabolism, and reduce excessive lipid accumulation in the pancreas. Furthermore, expression of AMPKα and downstream uncoupling protein 1 were upregulated, while genes related to mammalian target of rapamycin complex 1 (mTORC1) signal pathway and lipid de novo synthesis were suppressed in HFD-BCAA restriction group compared with HFD and HFD-high BCAAs fed mice. In addition, BCAA restriction upregulated expression of BCAAs related metabolic enzymes including PPM1K and BCKDHA, and decreased the levels of BCAAs and branched chain keto acid in the pancreas. However, there was no difference in levels of lipid content in the pancreas and gene expression of AMPKα and mTORC1 between HFD and HFD-high BCAAs groups. Branched-chain amino acid restriction ameliorated HFD-induced NAFPD in mice by activation of AMPKα pathway and suppression of mTORC1 pathway.

Acute Exposure to Branched-Chain Amino Acids (BCAAs) Impairs Glucose Homeostasis by Promoting Insulin Resistance in Mice

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10−4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice’s weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Background B0AT1 (SLC6A19) mediates the reabsorption of neutral amino acids, including branched-chain amino acids (BCAA), in the intestine and kidney (expressed in early and mid-proximal tubule - S1/S2). Dietary restriction of BCAA has been proposed to improve metabolic health by inhibiting mTOR and inducing autophagy. Here we characterized basal kidney function and determined whether B0AT1 KO protects the kidney from aristolochic acid-induced nephropathy (AAN), a model of proximal tubular injury. Methods In male B0AT1 KO and littermate wild-type mice (WT) mice, we measured fractional renal amino acid excretion and performed renal FITC-sinistrin clearance studies under terminal anesthesia to determine renal creatinine handling. A set of female mice was injected with aristolochic acid (3 mg/kg i.p.) or vehicle every 3 days for 3 weeks, and kidneys were harvested 3 weeks later for RTqPCR analyses (n=7-16 mice per group). Results RTqPCR and Western blotting confirmed absence of renal B0AT1 mRNA in KO, associated with increased fractional renal excretion of neutral amino acids, including BCAA (to 20-40%), whereas plasma levels of BCAA were not changed. In vehicle-treated mice, plasma creatinine was slightly higher in KO vs WT (0.080±0.002 vs 0.074±0.002 mg/dl; *P<0.05). Clearance studies revealed a trend for lesser fractional excretion of creatinine in KO vs WT (P=0.057), suggesting lesser creatinine secretion contributed to higher plasma levels. Urinary albumin/creatinine ratio (UACR) and urinary glucose/creatinine ratio (UGCR) were tripled and doubled in female KO vs WT (180±18 vs 62±5 ng/μg*; 1.35±0.26 vs 0.70±0.06 mg/mg*), respectively, suggesting a modest impairment in proximal tubular albumin and glucose reabsorption. The renal expression of the alternative neutral amino acid transporter B0AT3 (SLC6A18), expressed in S1-S3, was reduced in KO (to 32±5% of WT*). This may be due to KO model generation, as B0AT1 and B0AT3 are co-expressed side-by-side on the same chromosome. Whole kidney CCR2 and KIM-1 mRNA expression were modestly higher in KO vs WT, which may reflect enhanced amino acid and glucose transport in the vulnerable S3 segment in the outer medulla. In the absence of robust effects on plasma creatinine, AAN significantly increased UACR vs vehicle in WT (+164±39 vs +52±14 ng/μg*) but not in KO (-18±30 vs +57±49 ng/μg) when measured after completion of injections. Moreover, increases in CCR2 and TIMP1 expression in response to AAN vs vehicle observed in WT (+206±28%; +203±45%) were attenuated in KO (+54±20%*; +81±39%*). Conclusions Genetic deletion of B0AT1 in male and female mice induces distinct effects on kidney transport beyond amino acids. Follow up studies with higher doses of AA are needed to more fully evaluate the nephroprotective potential of B0AT1 inhibition.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by mutations in any of the genes encoding for the branched-chain keto dehydrogenase (BCKDH) components. This study screened MSUD patients throughout the whole Upper Egypt describing their symptoms, clinical and laboratory findings, genetic studies, and their treatment, with a 6-month follow-up for their responses. Screening identified three children with MSUD. Homozygous mutation in R195Q single nucleotide polymorphism (SNP) within the BCKDHA gene was found with the second MSUD patient. Follow-up for 6 months to assess the treatment regimens and progression of cases demonstrated that early treatment regimens including a dietary restriction of branched-chain amino acids with L-Carnitine administration could prevent MSUD-associated intellectual disabilities. It was concluded that R195Q SNP is pathogenic, and it may cause inherited forms of MSUD in some patients. MSUD cases have rarely been reported; so these findings will be highly useful for future cases of MSUD in the Upper Egyptian population.

Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.

We present a one-year-old girl with maple syrup urine disease with dermatitis secondary to the restriction of amino acids as part of the treatment. We present the clinical evolution and histopathological correlation.

Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export

Abstract Leucinosis (maple syrup urine disease - MSUD) is an inherited aminoacidopathy and organic aciduria caused by severe enzyme defect in the metabolic pathway of amino acids: leucine, isoleucine, and valine. The classical variant of the disease is characterized by accumulation of both amino and α-keto acids, particulary the most toxic rapid elevation of circulating leucine and its ketoacid, α-ketoisocaproate, which cause encephalopathy and life-threatening brain swelling. However, patients with the most severe form, classical maple syrup urine disease, may appear normal at birth, but develop acute metabolic decompensation within the first weeks of life with typical symptoms: poor feeding, vomiting, poor weight gain, somnolence and burnt sugar-smelling urine, reminiscent of maple syrup. Early diagnosis and dietary intervention improve the patient’s condition, prevent severe complications, and may allow normal intellectual development. We present a 4-month old infant with leucinosis dignosed 3 months earlier, due to elevated levels of amino acids: leucine, isoleucine and valine. The patient was full-term neonate with an uncomplecated delivery, without any family history of metabolic disorder or consanguinity. The infant was referred to a dermatologist, because of maculopapular exanthema on the scalp, trunk, upper and lower extremities, and exfoliative dermatitis of the perioral, particularly anogenital regions, associated with diarrhea. Skin involvement was associated with poor general condition of the infant exhibiting severe hypotension, anemic syndrome, dyspepsia and neurological symptoms. Exanthema developed a few days after the initiation of nutritional therapy for MSUD: isoleucine-, leucine-, and valine-free powdered medical food (MSUD-2) supplemented with iron. Zink levels were within normal ranges. Rapid skin improvement occurred after adequate branched-chain amino acids supplementation was commenced under regular laboratory control (normal zinc serum level with deficiencies of leucine and valine), skin hygiene with antiseptics, emollients and low potent topical corticosteroids. Treatment of acute metabolic decompensation and dietary restriction of branched-chain amino acids are the main aspects in the management of maple syrup urine disease. Common findings in patients with MSUD include: plasma amino acid imbalance, particularly of essential amino acids, failure to thrive attributed to restriction of particular precursor amino acids and natural proteins, micronutrient deficiencies or higher energy requirement due to chronic illness or inflammation. Due to low intake of branched-chain amino acids, some patients develop skin lesions known as acrodermatitis enteropathica-like syndrome. Here we report a case of an infant who developed acrodermatitis enteropathica-like skin eruptions due to branched-chain amino acid deficiency during treatment of maple syrup urine disease. According to available world literature, this is the first report of acrodermatitis enteropathica-like syndrome in an infant with maple syrup urine disease (leucinosis) in the Republic of Bulgaria.

Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase (BCKDH) complex. This disease is currently treated primarily by dietary restriction of branched-chain amino acids (BCAAs). However, dietary compliance is often challenging. Conversely, liver transplantation significantly improves outcomes, but donor organs are scarce and there are high costs and potential risks associated with this invasive procedure. Therefore, improved treatment options for MSUD are needed. Development of novel treatments could be facilitated by animal models that accurately mimic the human disease. Animal models provide a useful system in which to explore disease mechanisms and new preclinical therapies. Here we review MSUD and currently available animal models and their corresponding relevance to the human disorder. Using animal models to gain a more complete understanding of the pathophysiology behind the human disease may lead to new or improved therapies to treat or potentially cure the disorder.

After completing this article, readers should be able to: 1. List the major categories of diseases detectable by expanded newborn screening. 2. Give examples of the benefits and limitations of screening by tandem mass spectrometry. 3. Describe the appropriate follow-up for an abnormal screening result. The screening of newborns for inherited metabolic disorders is a well-established public health activity, first implemented in the early 1960s for the presymptomatic identification of patients who have phenylketonuria (PKU). Since then, significant technological advances, most importantly the development of tandem mass spectrometry (MS/MS), have enabled the detection of an increasing number of metabolic disorders in newborn blood. This article reviews the basic technology of MS/MS and its application to newborn screening, with the aim of highlighting the benefits and pointing out some limitations of this powerful technology. Early screening for PKU used the bacterial inhibition assay of Guthrie, in which inhibition of bacterial growth on an agar medium, introduced by the addition of a phenylalanine analog, was overcome by the presence of dried blood discs containing high levels of phenylalanine (such as from a PKU patient). This approach later was adapted for the detection of leucine in patients who have maple syrup urine disease (MSUD), methionine in patients who have classic homocystinuria, and tyrosine in patients who have tyrosinemia. Over the years, other techniques have been implemented to screen for additional disorders, including congenital hypothyroidism, biotinidase deficiency, galactosemia, hemoglobinopathies, and congenital adrenal hyperplasia. The classic criteria used to determine whether a disorder is suitable for screening include: 1) the disorder is clinically and biochemically well defined, 2) it is associated with significant morbidity or mortality, 3) an effective treatment is available, and 4) there is a simple and safe screening test. (1) By the early 1990s, all states offered screening for at least PKU and congenital hypothyroidism, …

Leigh disease with deficiency of lipoamide dehydrogenase: Treatment failure with dichloroacetate

Acute illness in maple syrup urine disease: Dynamics of protein metabolism and implications for management

Branched chain alpha-ketoacid dehydrogenase (BCKAD) deficiency, or maple syrup urine disease (MSUD), can be categorized as classical, intermediate, intermittent or thiamine responsive, based on generally concordant in vitro BCKAD activity and severity of phenotype. We present clinical and enzymatic data on a boy with intermediate maple syrup urine disease, and suggest that he represents a novel category of mutation. He presented at age 10 months in ketoacidotic coma, with a history of irritability, poor feeding and growth and developmental delay. Branched chain amino acid restriction effected normal growth and developmental parameters by age 42 months. In contrast to previous patients with intermediate MSUD, his fibroblasts and fibroblast extracts failed to decarboxylate [1-14C]-alpha-ketoisovalerate (KIV). The defect is not in mitochondrial transport of substrate, but rather in the catalytic activity of the E1 component of the BCKAD. Disrupted cells of the proband exhibited negligible BCKAD activity over a wide range of keto acid substrate concentrations, irrespective of the presence of added thiamine pyrophosphate (TPP). These results differ from the sigmoidal kinetics observed using classical MSUD extracts, and the hyperbolic kinetics with control preparations under the same assay conditions. We propose that the structurally altered enzyme possesses reduced but not negligible activity in vivo, and exists as an unstable complex in vitro under assay conditions used, even in the presence of added TPP.

Studies of urinary organic acid profiles of a patient with dihydrolipoyl dehydrogenase deficiency

Gas chromatography-mass spectrometric studies of dihydrolipoyl dehydrogenase deficiency