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Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21

Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast gr...

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Autores principales: Klein Hazebroek, Marlou, Laterveer, Rutger, Kutschke, Maria, Ramšak Marčeta, Vida, Barthem, Clarissa S., Keipert, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290677/
https://www.ncbi.nlm.nih.gov/pubmed/37355753
http://dx.doi.org/10.1038/s41598-023-37264-0
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author Klein Hazebroek, Marlou
Laterveer, Rutger
Kutschke, Maria
Ramšak Marčeta, Vida
Barthem, Clarissa S.
Keipert, Susanne
author_facet Klein Hazebroek, Marlou
Laterveer, Rutger
Kutschke, Maria
Ramšak Marčeta, Vida
Barthem, Clarissa S.
Keipert, Susanne
author_sort Klein Hazebroek, Marlou
collection PubMed
description Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development.
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spelling pubmed-102906772023-06-26 Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21 Klein Hazebroek, Marlou Laterveer, Rutger Kutschke, Maria Ramšak Marčeta, Vida Barthem, Clarissa S. Keipert, Susanne Sci Rep Article Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development. Nature Publishing Group UK 2023-06-24 /pmc/articles/PMC10290677/ /pubmed/37355753 http://dx.doi.org/10.1038/s41598-023-37264-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Klein Hazebroek, Marlou
Laterveer, Rutger
Kutschke, Maria
Ramšak Marčeta, Vida
Barthem, Clarissa S.
Keipert, Susanne
Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title_full Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title_fullStr Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title_full_unstemmed Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title_short Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
title_sort hyperphagia of female ucp1-deficient mice blunts anti-obesity effects of fgf21
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290677/
https://www.ncbi.nlm.nih.gov/pubmed/37355753
http://dx.doi.org/10.1038/s41598-023-37264-0
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