PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity

  • Nature. 2024 Sep;633(8028):182-188. doi: 10.1038/s41586-024-07801-6.
Wei Wei  1  2 ,  Xuchao Lyu  1  2  3 ,  Andrew L Markhard  1  2 ,  Sipei Fu  1  2  4 ,  Rachel E Mardjuki  2  5  6 ,  Peter E Cavanagh  5 ,  Xianfeng Zeng  2  7 ,  Jakub Rajniak  2  7 ,  Nannan Lu  8  9 ,  Shuke Xiao  1  2 ,  Meng Zhao  1  10 ,  Maria Dolores Moya-Garzon  1  2  3 ,  Steven D Truong  1  2 ,  Jonathan Chiu-Chun Chou  6 ,  Lianna W Wat  1  10  11 ,  Saranya Chidambaranathan-Reghupaty  1  10  11 ,  Laetitia Coassolo  1  10  11 ,  Duo Xu  2  5 ,  Fangfang Shen  2  6 ,  Wentao Huang  12 ,  Cuauhtemoc B Ramirez  13 ,  Cholsoon Jang  13 ,  Lingyin Li  2  5  14 ,  Katrin J Svensson  1  10  11 ,  Michael A Fischbach  2  7 ,  Jonathan Z Long  15  16  17  18  19  20
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 3. Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • 4. Department of Biology, Stanford University, Stanford, CA, USA.
  • 5. Department of Biochemistry, Stanford University, Stanford, CA, USA.
  • 6. Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 7. Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 8. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • 9. Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 10. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
  • 11. Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 12. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 13. Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
  • 14. Arc Institute, Palo Alto, CA, USA.
  • 15. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 16. Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
  • 17. Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. [email protected].
  • 18. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 19. Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 20. The Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
PMID: 39112712 DOI: 10.1038/s41586-024-07801-6
Abstract

Taurine is a conditionally essential micronutrient and one of the most abundant Amino acids in humans1-3. In endogenous taurine metabolism, dedicated Enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the Enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced Obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

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