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

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 t...

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Autores principales: Haenisch, Michael, Ngyuen, Tai, Fihn, Conrad A., Goldstein, Alex S., Amory, John K., Treuting, Piper, Brabb, Thea, Paik, Jisun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238815/
https://www.ncbi.nlm.nih.gov/pubmed/33934107
http://dx.doi.org/10.1038/s41366-021-00818-1
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author Haenisch, Michael
Ngyuen, Tai
Fihn, Conrad A.
Goldstein, Alex S.
Amory, John K.
Treuting, Piper
Brabb, Thea
Paik, Jisun
author_facet Haenisch, Michael
Ngyuen, Tai
Fihn, Conrad A.
Goldstein, Alex S.
Amory, John K.
Treuting, Piper
Brabb, Thea
Paik, Jisun
author_sort Haenisch, Michael
collection PubMed
description 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 IC(50) 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.
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spelling pubmed-82388152021-11-01 Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity Haenisch, Michael Ngyuen, Tai Fihn, Conrad A. Goldstein, Alex S. Amory, John K. Treuting, Piper Brabb, Thea Paik, Jisun Int J Obes (Lond) Article 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 IC(50) 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. 2021-05-01 2021-07 /pmc/articles/PMC8238815/ /pubmed/33934107 http://dx.doi.org/10.1038/s41366-021-00818-1 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Haenisch, Michael
Ngyuen, Tai
Fihn, Conrad A.
Goldstein, Alex S.
Amory, John K.
Treuting, Piper
Brabb, Thea
Paik, Jisun
Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title_full Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title_fullStr Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title_full_unstemmed Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title_short Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
title_sort investigation of an aldh1a1-specific inhibitor for suppression of weight gain in a diet induced mouse model of obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238815/
https://www.ncbi.nlm.nih.gov/pubmed/33934107
http://dx.doi.org/10.1038/s41366-021-00818-1
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