@article{BishopMachateHenningetal.2022,
  author    = {Bishop, Christopher Allen and Machate, Tina and Henning, Thorsten and Henkel-Oberl{\"a}nder, Janin and P{\"u}schel, Gerhard and Weber, Daniela and Grune, Tilman and Klaus, Susanne and Weitkunat, Karolin},
  title     = {Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle},
  series = {Nutrition \& Diabetes},
  volume    = {12},
  journal   = {Nutrition \& Diabetes},
  number    = {1},
  publisher = {Nature Publishing Group},
  address   = {London},
  issn      = {2044-4052},
  doi       = {10.1038/s41387-022-00200-8},
  pages     = {9},
  year      = {2022},
  abstract  = {Objective: Current data regarding the roles of branched-chain amino acids (BCAA) in metabolic health are rather conflicting, as positive and negative effects have been attributed to their intake. Methods: To address this, individual effects of leucine and valine were elucidated in vivo (C57BL/6JRj mice) with a detailed phenotyping of these supplementations in high-fat (HF) diets and further characterization with in vitro approaches (C2C12 myocytes). Results: Here, we demonstrate that under HF conditions, leucine mediates beneficial effects on adiposity and insulin sensitivity, in part due to increasing energy expenditure-likely contributing partially to the beneficial effects of a higher milk protein intake. On the other hand, valine feeding leads to a worsening of HF-induced health impairments, specifically reducing glucose tolerance/ insulin sensitivity. These negative effects are driven by an accumulation of the valine-derived metabolite 3-hydroxyisobutyrate (3HIB). Higher plasma 3-HIB levels increase basal skeletal muscle glucose uptake which drives glucotoxicity and impairs myocyte insulin signaling. Conclusion: These data demonstrate the detrimental role of valine in an HF context and elucidate additional targetable pathways in the etiology of BCAA-induced obesity and insulin resistance.},
  language  = {en}
}