Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

Sjögren, R. J. O.; Rizo-Roca, D.; Chibalin, A. V.; Chorell, E.; Furrer, R.; Katayama, S.; Harada, J.; Karlsson, H. K. R.; Handschin, C.; Moritz, T.; Krook, A.; Näslund, E.; Zierath, J. R.

doi:10.1101/2020.07.24.218099

bioRxiv · 10.1101/2020.07.24.218099

Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

Sjögren, R. J. O.·Rizo-Roca, D.·Chibalin, A. V.·Chorell, E.·Furrer, R.·Katayama, S.·Harada, J.·Karlsson, H. K. R.·Handschin, C.·Moritz, T.·Krook, A.·Näslund, E.·Zierath, J. R.

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Abstract

Aims/hypothesisIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. MethodsPlasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific PGC-1 knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PGC-1A and ESRRA in the expression of the BCAA gene set. Radiolabeled leucine was used to analyze the impact of ERR knockdown on leucine oxidation. ResultsImpairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37-56% after an OGTT in the NGT group, whereas no changes were detected in individuals with T2D. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of BCAT2, BCKDH complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing PGC-1, 61% of the analyzed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific PGC-1 knockout mice. ESRRA (encoding estrogen-related receptor , ERR) silencing completely abrogated the PGC-1-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretationMetabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease of circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via a PGC-1 is ERR-dependent. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LICirculating levels of BCAA are elevated in type 2 diabetes. C_LIO_LIPGC-1 is involved in the transcription of the BCAA gene set. C_LI What is the key question?O_LIDoes metabolic inflexibility associated with type 2 diabetes encompass BCAA homeostasis and PGC-1 mediated transcription of the BCAA gene set? C_LI What are the new findings?O_LIBCAA homeostasis is further compromised by a glucose challenge in type 2 diabetes. C_LIO_LIAn OGTT reveals coordinated regulation between BCAA metabolites, blood glucose, and HbA1c levels. C_LIO_LIERR is essential for PGC-1-mediated BCAA gene expression in primary human myotubes. C_LI How might this impact on clinical practice in the foreseeable future?O_LIAn OGTT can be used to underscore impairments in BCAA metabolism. These findings suggest that interventions targeting the PGC-1/ ERR axis may improve BCAA homeostasis. C_LI

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Sjögren, R. J. O., Rizo-Roca, D., Chibalin, A. V., Chorell, E., Furrer, R., Katayama, S., Harada, J., Karlsson, H. K. R., Handschin, C., Moritz, T., Krook, A., Näslund, E., Zierath, J. R.. 2020-07-25. Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes. https://doi.org/10.1101/2020.07.24.218099

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