N-acetylaspartate availability is essential for juvenile survival on fat-free diet and determines metabolic health.
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.
['Hofer|Dina C|DC|', 'Zirkovits|Gabriel|G|', 'Pelzmann|Helmut J|HJ|', 'Huber|Katharina|K|', 'Pessentheiner|Ariane R|AR|', 'Xia|Wenmin|W|', 'Uno|Kyosuke|K|', 'Miyazaki|Toh|T|', 'Kon|Kanta|K|', 'Tsuneki|Hiroshi|H|', 'Pendl|Tobias|T|', 'Al Zoughbi|Wael|W|', 'Madreiter-Sokolowski|Corina T|CT|', 'Trausinger|Gert|G|', 'Abdellatif|Mahmoud|M|', 'Schoiswohl|Gabriele|G|', 'Schreiber|Renate|R|', 'Eisenberg|Tobias|T|', 'Magnes|Christoph|C|', 'Sedej|Simon|S|', 'Eckhardt|Matthias|M|', 'Sasahara|Masakiyo|M|', 'Sasaoka|Toshiyasu|T|', 'Nitta|Atsumi|A|', 'Hoefler|Gerald|G|', 'Graier|Wolfgang F|WF|', 'Kratky|Dagmar|D|', 'Auwerx|Johan|J|', 'Bogner-Strauss|Juliane G|JG|']
D000105:Acetyl Coenzyme A D000123:Acetyltransferases D017667:Adipocytes D000818:Animals D001224:Aspartic Acid D001921:Brain D018752:Diet, Fat-Restricted D004734:Energy Metabolism D007333:Insulin Resistance D008066:Lipolysis D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria
NAA insulin secretion acetyl-CoA adipose tissue energy homeostasis