Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity : Potential Involvement of Germ-Line microRNAs
Ribas-Aulinas, Francesc (Institut de Recerca Sant Joan de Déu)
Ribo, Sílvia (Institut de Recerca Sant Joan de Déu)
Casas Masnou, Eduard (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Mourin-Fernandez, Marta (Institut de Recerca Sant Joan de Déu)
Ramon-Krauel, Marta (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Diaz, Ruben (Institut de Recerca Sant Joan de Déu)
Lerin, Carles (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Kalko, Susana G. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vavouri, Tanya (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Jimenez-Chillaron, Josep C. (Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut)

Date:	2023
Abstract:	Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1.
Grants:	Agencia Estatal de Investigación SAF2017-84542-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Circadian rhythm ; Intergenerational epigenetic inheritance ; Childhood obesity ; Litter size ; Reduction ; DNA methylation ; Small non-coding RNAs
Published in:	Nutrients, Vol. 15 Núm. 5 (march 2023) , p. 1241, ISSN 2072-6643

DOI: 10.3390/nu15051241
PMID: 36904241

17 p, 2.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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