Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Animal Models

Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet-induced mouse model of obesity

International Journal of Obesity volume 45, pages 1542–1552 (2021)Cite this article

Subjects

Abstract

Background

Retinoic acid (RA) controls diverse physiological functions including weight regulation and energy metabolism. It has been reported that mice lacking ALDH1A1, one of the aldehyde dehydrogenases (ALDH) that synthesize RA, are healthy and resistant to weight gain, raising the possibility that inhibiting this enzyme might treat obesity. We previously demonstrated that treatment with a pan-ALDH1A enzyme inhibitor, WIN18446, suppressed weight gain in mice fed a high-fat diet (HFD), but caused increased hepatic lipidosis and reversible male infertility.

Methods

A series of piperazine compounds that inhibited ALDH1A1 were identified and their inhibitory activity was characterized in vitro using purified recombinant enzymes and cell-based assay systems. One potent compound, FSI-TN42 (N42) was examined for its oral bioavailability and pharmacodynamic effects. In addition, its effect on weight gain was investigated by daily oral administration to C57BL/6 male mice receiving a HFD, and compared with mice receiving WIN18446 or vehicle alone (n = 6/group, 200 mg compound/kg body weight) for 5 weeks. Body weights were measured weekly, and a glucose tolerance test was performed after 4 weeks of treatment. Tissues were collected to determine changes in adipose weight, hepatic lipidosis, retinoid metabolism, and expression of genes associated with RA and lipid metabolism.

Results

N42 irreversibly binds and inhibits ALDH1A1 in vitro with a low nM IC50 and 800-fold specificity for ALDH1A1 compared to ALDH1A2. Daily oral administration of N42 significantly suppressed weight gain (P < 0.05) and reduced visceral adiposity (p < 0.05) in mice fed a HFD without the hepatic lipidosis observed with WIN18446 treatment.

Conclusions

We developed a potent and specific inhibitor of ALDH1A1 that suppressed weight gain in mice fed a HFD. These findings demonstrate that inhibition of ALDH1A1 is a feasible target for drug development to treat and/or prevent obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Characterization of novel ALDH1A1 inhibitor, N42.
Fig. 2: Pharmacokinetics and pharmacodynamics of N42.
Fig. 3: Efficacy of N42 in reduction of weight gain in mice fed a HFD.
Fig. 4: Effects of N42 in hepatic lipidosis.
Fig. 5: Pharmacodynamic effects of N42 on RA synthesis in various tissues after 5 weeks of treatment.

Similar content being viewed by others

References

  1. Malnick SD, Knobler H. The medical complications of obesity. QJM. 2006;99:565–79.

    Article  CAS  Google Scholar 

  2. Apovian CM. Obesity: definition, comorbidities, causes, and burden. Am J Manag Care. 2016;22 7 Suppl:s176–85.

    PubMed  Google Scholar 

  3. Jackson VM, Breen DM, Fortin JP, Liou A, Kuzmiski JB, Loomis AK, et al. Latest approaches for the treatment of obesity. Expert Opin Drug Discov. 2015;10:825–39.

    Article  CAS  Google Scholar 

  4. Kushner RF. Weight loss strategies for treatment of obesity: lifestyle management and pharmacotherapy. Prog Cardiovasc Dis. 2018;61:246–52.

    Article  Google Scholar 

  5. Velazquez A, Apovian CM. Updates on obesity pharmacotherapy. Ann N Y Acad Sci. 2018;1411:106–19.

    Article  Google Scholar 

  6. Blaner WS. Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders. Pharmacol Ther. 2019;197:153–78.

    Article  CAS  Google Scholar 

  7. Zhang R, Wang Y, Li R, Chen G. Transcriptional factors mediating retinoic acid signals in the control of energy metabolism. Int J Mol Sci. 2015;16:14210–44.

    Article  CAS  Google Scholar 

  8. Cañete A, Cano E, Muñoz-Chápuli R, Carmona R. Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis. Nutrients. 2017;9:159.

    Article  Google Scholar 

  9. Pino-Lagos K, Benson MJ, Noelle RJ. Retinoic acid in the immune system. Ann N Y Acad Sci. 2008;1143:170–87.

    Article  CAS  Google Scholar 

  10. Ghyselinck NB, Duester G. Retinoic acid signaling pathways. Development. 2019;146:dev167502.

    Article  Google Scholar 

  11. Yadu N, Kumar PG. Retinoic acid signaling in regulation of meiosis during embryonic development in mice. Genesis. 2019;57:e23327.

    PubMed  Google Scholar 

  12. Teletin M, Vernet N, Ghyselinck NB, Mark M. Roles of retinoic acid in germ cell differentiation. Curr Top Dev Biol. 2017;125:191–225.

    Article  CAS  Google Scholar 

  13. Kiefer FW, Vernochet C, O’Brien P, Spoerl S, Brown JD, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med. 2012;18:918–25.

    Article  CAS  Google Scholar 

  14. Yang D, Krois CR, Huang P, Wang J, Min J, Yoo HS, et al. Raldh1 promotes adiposity during adolescence independently of retinal signaling. PLoS ONE. 2017;12:e0187669.

    Article  Google Scholar 

  15. Ziouzenkova O, Orasanu G, Sharlach M, Akiyama TE, Berger JP, Viereck J, et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med. 2007;13:695–702.

    Article  CAS  Google Scholar 

  16. Haenisch M, Treuting PM, Brabb T, Goldstein AS, Berkseth K, Amory JK, et al. Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract. 2018;12:93–101.

    Article  Google Scholar 

  17. Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, et al. Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem. 2014;289:15104–17.

    Article  CAS  Google Scholar 

  18. Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, et al. Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res. 2015;56:342–57.

    Article  CAS  Google Scholar 

  19. Paik J, Fierce Y, Drivdahl R, Treuting PM, Seamons A, Brabb T, et al. Effects of murine norovirus infection on a mouse model of diet-induced obesity and insulin resistance. Comp Med. 2010;60:189–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, et al. Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl. 2011;32:111–9.

    Article  CAS  Google Scholar 

  21. Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, et al. Structural basis of ALDH1A2 inhibition by irreversible and reversible small molecule inhibitors. ACS Chem Biol. 2018;13:582–90.

    Article  CAS  Google Scholar 

  22. Lamb AL, Newcomer ME. The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity. Biochemistry. 1999;38:6003–11.

    Article  CAS  Google Scholar 

  23. Arnold SL, Kent T, Hogarth CA, Griswold MD, Amory JK, Isoherranen N. Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner. Biochem Pharmacol. 2015;95:177–92.

    Article  CAS  Google Scholar 

  24. Raverdeau M, Gely-Pernot A, Feret B, Dennefeld C, Benoit G, Davidson I, et al. Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis. Proc Natl Acad Sci USA. 2012;109:16582–7.

    Article  CAS  Google Scholar 

  25. Kane MA, Chen N, Sparks S, Napoli JL. Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem J. 2005;388:363–9.

    Article  CAS  Google Scholar 

  26. Kane MA, Folias AE, Wang C, Napoli JL. Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry. Anal Chem. 2008;80:1702–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute of Health (NIH) grant (R56 DK110239-01A1). Protein mass analysis was performed at Mass-Spectrometry Center (School of Pharmacy, UW) and liver histology was performed at Histology Imaging Core (Department of Comparative Medicine, UW).

Author information

Author notes

  1. Tai Nguyen

    Present address: Department of Chemistry, University of Southern California, Los Angeles, USA

  2. Conrad A. Fihn

    Present address: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, USA

Authors and Affiliations

  1. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    Michael Haenisch, Piper Treuting, Thea Brabb & Jisun Paik

  2. Focused Scientific, Newcastle, WA, USA

    Tai Nguyen, Conrad A. Fihn & Alex S. Goldstein

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    John K. Amory

Authors
  1. Michael Haenisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tai Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Conrad A. Fihn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alex S. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John K. Amory
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Piper Treuting
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thea Brabb
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jisun Paik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jisun Paik.

Ethics declarations

Conflict of interest

Authors (MH, ASG, JKA, PT, and JP) have filed a patent application (WO2020123855) for FSI-TN42. TN, CAF, and TB declare no potential competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haenisch, M., Nguyen, T., Fihn, C.A. et al. Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet-induced mouse model of obesity. Int J Obes 45, 1542–1552 (2021). https://doi.org/10.1038/s41366-021-00818-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-021-00818-1

This article is cited by

Search

Advanced search

Quick links