Branched chain amino acid metabolism and microbiome in adolescents with obesity during weight loss therapy
Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls
Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls
View: Text | PDF
Clinical Research and Public Health Clinical Research Metabolism Microbiology

Branched chain amino acid metabolism and microbiome in adolescents with obesity during weight loss therapy

Abstract

BACKGROUND Obesity and weight loss in adults have been associated with distinct metabolome and gut microbiome features, but the extent to which those associations apply to adolescent stages remain unclear.METHODS The Pediatric Obesity Microbiome and Metabolism Study (POMMS) enrolled 220 adolescents aged 10–18 with severe obesity (OB) and 67 individuals who were healthy weight controls (HWCs). Blood, stool, and clinical measures were collected at baseline and after a 6-month obesity intervention for the OB group. Metabolomic profiling in serum using targeted quantitative mass spectrometry and microbiome profiling in stool were performed, and those features were assessed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants (FMT) were performed on germ-free mice using samples from both groups to assess effects on weight gain and metabolic pathways.RESULTS Adolescents with OB exhibited higher serum branched-chain amino acid (BCAA) but lower branched-chain ketoacid (BCKA) levels compared with HWC. This pattern was sex- and age-dependent and differed from adults with obesity who show elevated levels of both BCAA and BCKA. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from both OB and HWC donors had similar effects on mouse body weight, but specific taxa were linked to weight gain in recipients of FMT.CONCLUSION Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared with their HWC counterparts and adults with OB.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository).FUNDING SUPPORT American Heart Association Grants: 17SFRN33670990, 20PRE35180195; National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.

Authors

Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls

×

Figure 2

Branched chain amino acids (BCAA) and related metabolite levels are sex dependent, significantly different in HWC v OB cohorts, and unique to adolescents with obesity.

Options: View larger image (or click on image) Download as PowerPoint
Branched chain amino acids (BCAA) and related metabolite levels are sex ...
(A) BCAA related metabolism pathway. Valine (VAL), Leucine (LEU) and Isoleucine (ILE) are reversibly transaminated by the branched chain amino acid transferase (BCAT2) in the mitochondria to their respective ketoacids ketoisovalerate (KIV), ketoisocaproate (KIC) and ketomethylvalerate (KMV). The amino group removed from the BCAA is transferred to α-ketoglutarate (α-KG), yielding glutamate (GLU). The ketoacids can then be irreversibly hydrolyzed by the branched chain ketoacid dehydrogenase (BCKDH) where BCAA-derived carbons can then enter the TCA cycle or contribute to lipogenesis. When BCAA are elevated, as in obesity, excess BCAA increases BCAT2 activity, which could result in an increased nitrogen load, especially in muscle tissues. This load can be relieved, most likely via coordinated action of serine dehydratase, serine hydroxymethyltransferase, and glycine acyltransferase. Resulting increased metabolites, such as glutamine (GLN) and acylglycine, can be secreted from the affected tissues. ALA, alanine; PYR, pyruvate. (B–J) Levels of serum amino acids and keto acids associated with BCAA and alanine-pyruvate metabolism in HWC versus OB cohorts divided by sex. Box plots represent mean and SD. Statistics were performed on mean metabolite values following log2 transformation, and P values result from Mann-Whitney tests and are corrected for multiple comparisons. **P < 0.01; ***P < 0.001; ****P < 0.0001.