Artículo
Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis
Autor/es | Roberti, Annalisa
Tejedor, Juan Ramón Díaz Moreno, Irene ![]() ![]() ![]() ![]() ![]() ![]() ![]() López, Virginia Santamarina-Ojeda, Pablo Pérez, Raúl F. Urdinguio, Rocío G. Concellón, Carmen Martínez-Chantar, María Luz Fernández Morera, Juan Luis Díaz Quintana, Antonio Jesús ![]() ![]() ![]() ![]() ![]() ![]() ![]() Amo, Vicente del Fernández, Agustín F. Fraga, Mario F. |
Departamento | Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular |
Fecha de publicación | 2023-05-22 |
Fecha de depósito | 2024-02-23 |
Publicado en |
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Resumen | Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of ... Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity. |
Agencias financiadoras | Principado de Asturias Instituto de Salud Carlos III Consejo Superior de Investigaciones Científicas (CSIC) Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía Ministerio de Ciencia, Innovación y Universidades (MICINN). España Fundación la Caixa Gobierno Vasco |
Identificador del proyecto | IDI/2018/146
![]() IDI/2021/000077 ![]() PI18/01527 ![]() PI21/01067 ![]() 202020E092 ![]() 0348_CIE_6_E ![]() SOLAUT_00038505 SGL2103040 ![]() SGL2021-03-39 ![]() SGL2021-03-040 ![]() PID2021-126663NB-100 ![]() CTQ2016- 76829-R ![]() PID2020-113473GB-I00 ![]() IJC2018-036825-I ![]() BIO198 ![]() P18-FR-3487 ![]() PID2020-117116RB-I00 ![]() RTC2019-007125-1 ![]() HR17-00601 ![]() KK-2020/00008 ![]() |
Cita | Roberti, A., Tejedor, J.R., Díaz Moreno, I., López, V., Santamarina-Ojeda, P., Pérez, R.F.,...,Fraga, M.F. (2023). Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis. Scientific Reports, 13 (1), 8293. https://doi.org/10.1038/s41598-023-34916-z. |
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Nicotinamide.pdf | 8.757Mb | ![]() | Ver/ | Versión publicada |