1. N ‐acetylaspartate availability is essential for juvenile survival on fat‐free diet and determines metabolic health
- Author
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Wolfgang F. Graier, Tobias Pendl, Dagmar Kratky, Dina Hofer, Renate Schreiber, Wael Al Zoughbi, Kyosuke Uno, Masakiyo Sasahara, Hiroshi Tsuneki, Gabriele Schoiswohl, Kanta Kon, Toshiyasu Sasaoka, Toh Miyazaki, Johan Auwerx, Katharina Huber, Tobias Eisenberg, Juliane G. Bogner-Strauss, Gabriel Zirkovits, Ariane Pessentheiner, Corina T. Madreiter-Sokolowski, Wenmin Xia, Matthias Eckhardt, Gerald Hoefler, Atsumi Nitta, Christoph Magnes, Gert Trausinger, Simon Sedej, Helmut Josef Pelzmann, and Mahmoud Abdellatif
- Subjects
naa ,0301 basic medicine ,insulin secretion ,medicine.medical_specialty ,brain ,Metabolite ,Adipose tissue ,Biology ,Biochemistry ,Energy homeostasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Internal medicine ,Adipocyte ,mental disorders ,l-aspartic acid ,Respiration ,brown adipose-tissue ,magnetic-resonance-spectroscopy ,follow-up ,Genetics ,medicine ,toxicity assessment ,Lipolysis ,glucose ,atgl-mediated lipolysis ,energy homeostasis ,Molecular Biology ,2. Zero hunger ,Research ,acetyl-coa ,Lipid metabolism ,deficiency ,nervous system diseases ,adipose tissue ,030104 developmental biology ,Endocrinology ,nervous system ,chemistry ,beta-cell line ,Lipogenesis ,030217 neurology & neurosurgery ,Biotechnology - Abstract
N-acetylaspartate (NAA) is synthesized by aspartate N-acetyltransferase (gene: Nat8l) from acetyl–coenzyme A and aspartate. In the brain, NAA is considered an important energy metabolite for lipid synthesis. However, the role of NAA in peripheral tissues remained elusive. Therefore, we characterized the metabolic phenotype of knockout (ko) and adipose tissue–specific (ako) Nat8l-ko mice as well as NAA-supplemented mice on various diets. We identified an important role of NAA availability in the brain during adolescence, as 75% of Nat8l-ko mice died on fat-free diet (FFD) after weaning but could be rescued by NAA supplementation. In adult life, NAA deficiency promotes a beneficial metabolic phenotype, as Nat8l-ko and Nat8l-ako mice showed reduced body weight, increased energy expenditure, and improved glucose tolerance on chow, high-fat, and FFDs. Furthermore, Nat8l-deficient adipocytes exhibited increased mitochondrial respiration, ATP synthesis, and an induction of browning. Conversely, NAA-treated wild-type mice showed reduced adipocyte respiration and lipolysis and increased de novo lipogenesis, culminating in reduced energy expenditure, glucose tolerance, and insulin sensitivity. Mechanistically, our data point to a possible role of NAA as modulator of pancreatic insulin secretion and suggest NAA as a critical energy metabolite for adipocyte and whole-body energy homeostasis.—Hofer, D. C., Zirkovits, G., Pelzmann, H. J., Huber, K., Pessentheiner, A. R., Xia, W., Uno, K., Miyazaki, T., Kon, K., Tsuneki, H., Pendl, T., Al Zoughbi, W., Madreiter-Sokolowski, C. T., Trausinger, G., Abdellatif, M., Schoiswohl, G., Schreiber, R., Eisenberg, T., Magnes, C., Sedej, S., Eckhardt, M., Sasahara, M., Sasaoka, T., Nitta, A., Hoefler, G., Graier, W. F., Kratky, D., Auwerx, J., Bogner-Strauss, J. G. N-acetylaspartate availability is essential for juvenile survival on fat-free diet and determines metabolic health.
- Published
- 2019
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