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

Wei Wei; Xuchao Lyu; Andrew L Markhard; Sipei Fu; Rachel E Mardjuki; Peter E Cavanagh; Xianfeng Zeng; Jakub Rajniak; Nannan Lu; Shuke Xiao; Meng Zhao; Maria Dolores Moya-Garzon; Steven D Truong; Jonathan Chiu-Chun Chou; Lianna W Wat; Saranya Chidambaranathan-Reghupaty; Laetitia Coassolo; Duo Xu; Fangfang Shen; Wentao Huang; Cuauhtemoc B Ramirez; Cholsoon Jang; Lingyin Li; Katrin J Svensson; Michael A Fischbach; Jonathan Z Long

doi:10.1038/s41586-024-07801-6

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. Epub 2024 Aug 7.

Authors

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 Cavanagh⁵, 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 Chou⁶, 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 Huang¹², Cuauhtemoc B Ramirez¹³, Cholsoon Jang¹³, 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].

Abstract

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans^1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites^4,5. 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 consumption^6,9. 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.

MeSH terms

Acetic Acid / metabolism
Animals
Body Mass Index
Body Weight*
Brain Stem / metabolism
Carrier Proteins / genetics
Carrier Proteins / metabolism
Eating* / physiology
Energy Metabolism
Exercise
Female
Glucose / metabolism
Homeostasis
Humans
Hydrolases* / deficiency
Hydrolases* / genetics
Hydrolases* / metabolism
Hydrolysis
Kidney / metabolism
Liver / enzymology
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity* / enzymology
Obesity* / metabolism
Secondary Metabolism
Taurine* / analogs & derivatives
Taurine* / metabolism
Weight Loss

Substances

Glucose
Hydrolases
Taurine
PTER protein, human
Carrier Proteins
Acetic Acid
GFRAL protein, mouse
acetyltaurine

Abstract

MeSH terms

Substances

Grants and funding