AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.8441
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ORIGINAL RESEARCH ARTICLE

Epigenetic regulation role of SUV420H in sexual dimorphism of adipose tissue and obesity

Carmela Asteria1 ,  Roberta Caccia2 ,  Alessandro Giovanelli1 ,  Arianna Segaloni2,3 ,  Giorgia Scichilone1 ,  Alexis Elias Malavazos4 ,  Lelio Morricone4 ,  Danilo Parolini5 ,  Davide Gabellini2* ,  Simona Pedrotti2,6*
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1 National Institute for Obesity Cure, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
2 Gene Expression Regulation Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
3 Università degli Studi Milano Bicocca, Milan, Italy
4 Endocrinology Unit, Clinical Nutrition and Cardiovascular Prevention Service, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
5 Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
6 Fondazione Human Technopole, Viale Rita Levi-Montalcini 1, Milan, Italy
GPD, 8441 https://doi.org/10.36922/gpd.8441
Received: 7 January 2025 | Revised: 5 August 2025 | Accepted: 7 August 2025 | Published online: 28 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Obesity is a worldwide health crisis linked to numerous harmful medical conditions. It arises from complex interactions between behavioral, environmental, and genetic factors. Interestingly, there is evidence of sexual dimorphism in the function of mitochondrial activity and metabolic flexibility of adipose tissue in obesity. Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a critical factor in the formation of fat cells, glucose processing, and fat production, plays an essential role in the onset of obesity. Recently, it has been implicated in sex-based differences in adipose tissue gene expression and fat distribution. Epigenetic modifications mediate the effects of environmental factors by controlling the activity of genes related to metabolism. SUV420H1 and SUV420H2, histone methyltransferases that catalyze the addition of di- and trimethyl groups to lysine 20 of histone H4, suppress gene expression. Previous research has shown that SUV420H proteins respond to environmental signals by directly repressing PPAR-γ activity. In this study, we demonstrated that SUV420H1 and SUV420H2 are expressed differently between sexes in both human and mouse models. Interestingly, mice with a double knockout of Suv420h1 and Suv420h2 exhibit a sex-specific difference in their resistance to diet-induced obesity. Gene expression analysis of adipose tissue samples from obese humans reveals a significant inverse relationship between SUV420H and PPAR-γ expression in females, while no such correlation is observed in males. These findings highlight a potentially novel role for SUV420H proteins in modulating PPAR-γ activity, metabolic function, and the risk of obesity, with a clear sexual dimorphism in their effects.

Graphical abstract
Keywords
Epigenetics
Obesity
Sex
Adipose tissue
Gene expression
Funding
Research in D.G.’s laboratory was supported by the Italian Ministry of Health (grant number RF-2018-12366631), the European Joint Program on Rare Diseases (grant number EJPRD20-191), the Italian Association for Cancer Research (grant number IG 2017-ID. 19919), and the National Institutes of Health—National Cancer Institute (grant number 1R21CA249378-01). S.P. was supported by the Italian Ministry of Health (grant number GR-2018- 12365314).
Conflict of interest
The authors declare that they have no competing interests.
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