Exercise-induced N-lactoyl-phenylalanine, appetite and obesity

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N-lactoyl-phenylalanine (Lac-Phe) is a blood plasma metabolite present at elevated levels during recovery from high-intensity exercise. In a study with obese mice, presence of this metabolite suppresses feeding. On the other hand, genetically removing the enzyme responsible for its synthesis leads to obesity in mice when offering high-fat kibble. [1]

Contents

Background

Regulation of metabolism is complex, happens at different time scales, and is known to involve hormones such as insulin, glucagon, ghrelin and leptin. Exercise is known to induce several plasma metabolites, which might be part of the mechanisms that confer health benefits.[2] N-lactoyl-amino acids had been discovered in processed food, acting as flavor and mouthfeel compounds (summarized in [3], study specifically on taste of Lac-Phe [4]). In 2015, the biosynthesis of N-lactoyl-amino acids was described by Robert S. Jansen et al [5]. These metabolites can form inside living cells through the action of the protease CNDP2 [6], and are then found in the blood plasma. High concentrations of lactate or amino acids result in high concentrations of the N-lactoyl-amino acids. N-lactoyl-phenylalanine is now suspected to have a role in appetite regulation[1]. According to Barry Braun cited in the New York Times[7], "We always knew that our current menu of molecules that appear to regulate appetite and food intake, such as leptin, ghrelin, etc., was incomplete and this new metabolite/signaling molecule is a potentially important addition to that list."

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Structure

N-lactoyl-phenylalanine is a condensation product of lactate () and phenylalanine (). At physiological pH, it is expected to have a negative charge, making it more soluble than free phenylalanine.

Ingesting Lac-Phe has no effect

When mice were given Lac-Phe orally, there was no effect[1]. It is likely that the peptide bond linking lactate and phenylalanine would be hydrolyzed in the digestive tract, so it would not reach the blood stream. In a study on the related Lac-Leu, it was found that hydrolysis was efficient and dependent on enzymes [3].

References

  1. ↑ 1.0 1.1 1.2 Li VL, He Y, Contrepois K, Liu H, Kim JT, Wiggenhorn AL, Tanzo JT, Tung AS, Lyu X, Zushin PH, Jansen RS, Michael B, Loh KY, Yang AC, Carl CS, Voldstedlund CT, Wei W, Terrell SM, Moeller BC, Arthur RM, Wallis GA, van de Wetering K, Stahl A, Kiens B, Richter EA, Banik SM, Snyder MP, Xu Y, Long JZ. An exercise-inducible metabolite that suppresses feeding and obesity. Nature. 2022 Jun;606(7915):785-790. doi: 10.1038/s41586-022-04828-5. Epub 2022, Jun 15. PMID:35705806 doi:http://dx.doi.org/10.1038/s41586-022-04828-5
  2. ↑ Yang YR, Kwon KS. Potential Roles of Exercise-Induced Plasma Metabolites Linking Exercise to Health Benefits. Front Physiol. 2020 Dec 3;11:602748. doi: 10.3389/fphys.2020.602748. eCollection , 2020. PMID:33343398 doi:http://dx.doi.org/10.3389/fphys.2020.602748
  3. ↑ 3.0 3.1 Schmidt C, Wehsling M, Le Mignon M, Wille G, Rey Y, Schnellbaecher A, Zabezhinsky D, Fischer M, Zimmer A. Lactoyl leucine and isoleucine are bioavailable alternatives for canonical amino acids in cell culture media. Biotechnol Bioeng. 2021 Sep;118(9):3395-3408. doi: 10.1002/bit.27755. Epub 2021, Apr 8. PMID:33738790 doi:http://dx.doi.org/10.1002/bit.27755
  4. ↑ Wu J, Gao J, Lin J, Cui C, Li L, He S, Brennan C. Preparation and Taste Characteristics of Kokumi N-Lactoyl Phenylalanine in the Presence of Phenylalanine and Lactate. J Agric Food Chem. 2022 May 4;70(17):5396-5407. doi: 10.1021/acs.jafc.2c00530., Epub 2022 Apr 22. PMID:35452224 doi:http://dx.doi.org/10.1021/acs.jafc.2c00530
  5. ↑ Jansen RS, Addie R, Merkx R, Fish A, Mahakena S, Bleijerveld OB, Altelaar M, IJlst L, Wanders RJ, Borst P, van de Wetering K. N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6601-6. doi:, 10.1073/pnas.1424638112. Epub 2015 May 11. PMID:25964343 doi:http://dx.doi.org/10.1073/pnas.1424638112
  6. ↑ Andreyeva EN, Ogienko AA, Dubatolova TD, Oshchepkova AL, Kozhevnikova EN, Ivankin AV, Pavlova GA, Kopyl SA, Pindyurin AV. A toolset to study functions of Cytosolic non-specific dipeptidase 2 (CNDP2) using Drosophila as a model organism. BMC Genet. 2019 Mar 18;20(Suppl 1):31. doi: 10.1186/s12863-019-0726-z. PMID:30885138 doi:http://dx.doi.org/10.1186/s12863-019-0726-z
  7. ↑ Reynolds G (15 June 2022). "Why Does a Hard Workout Make You Less Hungry?". The New York Times. Retrieved 14 July 2022. https://www.nytimes.com/2022/06/15/well/move/exercise-appetite.html?smid=url-share

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