Pedrotti, SimonaCaccia, RobertaNeguembor, Maria VictoriaGarcía Manteiga, José ManuelFerri, GiuliaPalma, Clara deCanu, TamaraGiovarelli, MatteoMarra, PaoloFiocchi, AmletoMolineris, IvanRaso, MicheleSanvito, FrancescaDoglioni, ClaudioEsposito, AntonioClementi, EmilioGabellini, Davide2020-04-072020-04-072019Pedrotti S, Caccia R, Neguembor MV, Garcia-Manteiga JM, Ferri G, de Palma C, Canu T, Giovarelli M, Marra P, Fiocchi A, Molineris I, Raso M, Sanvito F, Doglioni C, Esposito A, Clementi E, Gabellini D. The Suv420h histone methyltransferases regulate PPAR-γ and energy expenditure in response to environmental stimuli. Sci Adv. 2019; 5(4):eaav1472. DOI: 10.1126/sciadv.aav14722375-2548http://hdl.handle.net/10230/44180Obesity and its associated metabolic abnormalities have become a global emergency with considerable morbidity and mortality. Epidemiologic and animal model data suggest an epigenetic contribution to obesity. Nevertheless, the cellular and molecular mechanisms through which epigenetics contributes to the development of obesity remain to be elucidated. Suv420h1 and Suv420h2 are histone methyltransferases responsible for chromatin compaction and gene repression. Through in vivo, ex vivo, and in vitro studies, we found that Suv420h1 and Suv420h2 respond to environmental stimuli and regulate metabolism by down-regulating peroxisome proliferator-activated receptor gamma (PPAR-γ), a master transcriptional regulator of lipid storage and glucose metabolism. Accordingly, mice lacking Suv420h proteins activate PPAR-γ target genes in brown adipose tissue to increase mitochondria respiration, improve glucose tolerance, and reduce adipose tissue to fight obesity. We conclude that Suv420h proteins are key epigenetic regulators of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.application/pdfeng© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.aav1472info:eu-repo/semantics/openAccess